Heterocyclic compounds as immunomodulators

ABSTRACT

Disclosed are compounds of Formula (I), methods of using the compounds as immunomodulators, and pharmaceutical compositions comprising such compounds. The compounds are useful in treating, preventing or ameliorating diseases or disorders such as cancer or infections.

FIELD OF THE INVENTION

The present application is concerned with pharmaceutically activecompounds. The disclosure provides compounds as well as theircompositions and methods of use. The compounds modulate PD-1/PD-L1protein/protein interaction and are useful in the treatment of variousdiseases including infectious diseases and cancer.

BACKGROUND OF THE INVENTION

The immune system plays an important role in controlling and eradicatingdiseases such as cancer. However, cancer cells often develop strategiesto evade or to suppress the immune system in order to favor theirgrowth. One such mechanism is altering the expression of co-stimulatoryand co-inhibitory molecules expressed on immune cells (Postow et al, J.Clinical Oncology 2015, 1-9). Blocking the signaling of an inhibitoryimmune checkpoint, such as PD-1, has proven to be a promising andeffective treatment modality.

Programmed cell death-1 (PD-1), also known as CD279, is a cell surfacereceptor expressed on activated T cells, natural killer T cells, Bcells, and macrophages (Greenwald et al, Annu. Rev. Immunol 2005,23:515-548; Okazaki and Honjo, Trends Immunol 2006, (4):195-201). Itfunctions as an intrinsic negative feedback system to prevent theactivation of T-cells, which in turn reduces autoimmunity and promotesself-tolerance. In addition, PD-1 is also known to play a critical rolein the suppression of antigen-specific T cell response in diseases likecancer and viral infection (Sharpe et al, Nat Immunol 2007 8, 239-245;Postow et al, J. Clinical Oncol 2015, 1-9).

The structure of PD-1 consists of an extracellular immunoglobulinvariable-like domain followed by a transmembrane region and anintracellular domain (Parry et al, Mol Cell Biol 2005, 9543-9553). Theintracellular domain contains two phosphorylation sites located in animmunoreceptor tyrosine-based inhibitory motif and an immunoreceptortyrosine-based switch motif, which suggests that PD-1 negativelyregulates T cell receptor-mediated signals. PD-1 has two ligands, PD-L1and PD-L2 (Parry et al, Mol Cell Biol 2005, 9543-9553; Latchman et al,Nat Immunol 2001, 2, 261-268), and they differ in their expressionpatterns. PD-L1 protein is upregulated on macrophages and dendriticcells in response to lipopolysaccharide and GM-CSF treatment, and on Tcells and B cells upon T cell receptor and B cell receptor signaling.PD-L1 is also highly expressed on almost all tumor cells, and theexpression is further increased after IFN-γ treatment (Iwai et al,PNAS2002, 99(19):12293-7; Blank et al, Cancer Res 2004, 64(3):1140-5).In fact, tumor PD-L1 expression status has been shown to be prognosticin multiple tumor types (Wang et al, Eur J Surg Oncol 2015; Huang et al,Oncol Rep 2015; Sabatier et al, Oncotarget 2015, 6(7): 5449-5464). PD-L2expression, in contrast, is more restricted and is expressed mainly bydendritic cells (Nakae et al, J Immunol 2006, 177:566-73). Ligation ofPD-1 with its ligands PD-L1 and PD-L2 on T cells delivers a signal thatinhibits IL-2 and IFN-γ production, as well as cell proliferationinduced upon T cell receptor activation (Carter et al, Eur J Immunol2002, 32(3):634-43; Freeman et al, J Exp Med 2000, 192(7):1027-34). Themechanism involves recruitment of SHP-2 or SHP-1 phosphatases to inhibitT cell receptor signaling such as Syk and Lck phosphorylation (Sharpe etal, Nat Immunol 2007, 8, 239-245). Activation of the PD-1 signaling axisalso attenuates PKC-θ activation loop phosphorylation, which isnecessary for the activation of NF-κB and AP1 pathways, and for cytokineproduction such as IL-2, IFN-γ and TNF (Sharpe et al, Nat Immunol 2007,8, 239-245; Carter et al, Eur J Immunol 2002, 32(3):634-43; Freeman etal, J Exp Med 2000, 192(7):1027-34).

Several lines of evidence from preclinical animal studies indicate thatPD-1 and its ligands negatively regulate immune responses.PD-1-deficient mice have been shown to develop lupus-likeglomerulonephritis and dilated cardiomyopathy (Nishimura et al, Immunity1999, 11:141-151; Nishimura et al, Science 2001, 291:319-322). Using anLCMV model of chronic infection, it has been shown that PD-1/PD-L1interaction inhibits activation, expansion and acquisition of effectorfunctions of virus-specific CD8 T cells (Barber et al, Nature 2006, 439,682-7). Together, these data support the development of a therapeuticapproach to block the PD-1-mediated inhibitory signaling cascade inorder to augment or “rescue” T cell response. Accordingly, there is aneed for new compounds that block PD-1/PD-L1 protein/proteininteraction.

SUMMARY

The present disclosure provides, inter alia, a compound of Formula (I):

or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinconstituent variables are defined herein.

The present disclosure further provides a pharmaceutical compositioncomprising a compound of the disclosure, or a pharmaceuticallyacceptable salt or a stereoisomer thereof, and at least onepharmaceutically acceptable carrier or excipient.

The present disclosure further provides methods of modulating orinhibiting PD-1/PD-L1 protein/protein interaction, which comprisesadministering to an individual a compound of the disclosure, or apharmaceutically acceptable salt or a stereoisomer thereof.

The present disclosure further provides methods of treating a disease ordisorder in a patient comprising administering to the patient atherapeutically effective amount of a compound of the disclosure, or apharmaceutically acceptable salt or a stereoisomer thereof.

DETAILED DESCRIPTION I. Compounds

The present disclosure provides a compound of Formula (I):

or a pharmaceutically acceptable salt or a stereoisomer thereof,wherein:

X¹ is O, S, N, NR¹ or CR¹;

X² is N or C;

X³ is O, S, N, NR³ or CR³;

X⁴ is N or CR⁴;

X⁵ is N or CR⁵;

X⁶ is N or CR⁶;

Y is C or N;

at least one of X¹, X², X³ and Y is a heteroatom selected from N, O andS;

Cy is C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5- to 14-membered heteroaryl, or 4-to 10-membered heterocycloalkyl, each of which is optionally substitutedwith 1 to 5 independently selected substituents;

R¹, R³, R⁴, R⁵ and R⁶ are each independently selected from H, C₁₋₄alkyl, C₃₋₄ cycloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, halo, CN, OH, C₁₋₄alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, NH₂, —NH—C₁₋₄ alkyl, —N(C₁₋₄alkyl)₂, NHOR¹⁰, C(O)R¹⁰, C(O)NR¹⁰R¹⁰, C(O)OR¹⁰, OC(O)R¹⁰, OC(O)NR¹⁰R¹⁰,NR¹⁰C(O)R¹⁰, NR¹⁰C(O)OR¹⁰, NR¹⁰C(O)NR¹⁰R¹⁰, C(═NR¹⁰)R¹⁰,C(═NR¹⁰)NR¹⁰R¹⁰, NR¹⁰C(═NR¹⁰) NR¹⁰R¹⁰, NR¹⁰S(O)R¹⁰, NR¹⁰S(O)₂R¹⁰,NR¹⁰S(O)₂NR¹⁰R¹⁰, S(O)R¹⁰, S(O)NR¹⁰R¹⁰, S(O)₂R¹⁰, and S(O)₂NR¹⁰R¹⁰,wherein each R¹⁰ is independently selected from H and C₁₋₄ alkyloptionally substituted with 1 or 2 groups independently selected fromhalo, OH, CN and C₁₋₄ alkoxy; and wherein the C₁₋₄ alkyl, C₃₋₄cycloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl and C₁₋₄ alkoxy of R¹, R³, R⁴, R⁵and R⁶ are each optionally substituted with 1 or 2 substituentsindependently selected from halo, OH, CN and C₁₋₄ alkoxy;

R⁹ is C₁₋₄ alkyl, halo, CN, OH, cyclopropyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, NH₂, —NH—C₁₋₄ alkyl,—N(C₁₋₄ alkyl)₂, NHOR¹¹, C(O)R¹¹, C(O)NR¹¹R¹¹, C(O)OR¹¹, OC(O)R¹¹,OC(O)NR¹¹R¹¹, NR¹¹C(O)R¹¹, NR¹¹C(O)OR¹¹, NR¹¹C(O)NR¹¹R¹¹, C(═NR¹¹)R¹¹,C(═NR¹¹)NR¹¹R¹¹, NR¹¹C(═NR¹¹)NR¹¹R¹¹, NR¹¹S(O)R¹¹, NR¹¹S(O)₂R¹¹,NR¹¹S(O)₂NR¹¹R¹¹, S(O)R¹¹, S(O)NR¹¹R¹¹, S(O)₂R¹¹, and S(O)₂NR¹¹R¹¹,wherein C₁₋₄ alkyl, cyclopropyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl and C₁₋₄alkoxy of R⁹ are each optionally substituted with 1 or 2 substituentsselected from halo, OH, CN and OCH₃ and each R¹¹ is independentlyselected from H and C₁₋₄ alkyl optionally substituted with 1 or 2 halo,OH, CN or OCH₃ substituents;

R⁷, R¹³ and R¹⁴ are each independently selected from H, halo, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a), SR^(a), NHOR^(a),C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a), OC(O)NR^(a)R^(a),NHR^(a), NR^(a)R^(a), NR^(a)C(O)R^(a), NR^(a)C(O)OR^(a),NR^(a)C(O)NR^(a)R^(a), C(═NR^(a))R^(a), C(═NR^(a))NR^(a)R^(a),NR^(a)C(═NR^(a))NR^(a)R^(a), NR^(a)S(O)R^(a), NR^(a)S(O)₂R^(a),NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a), S(O)₂R^(a), andS(O)₂NR^(a)R^(a), where in the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-14 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R⁷, R¹³ and R¹⁴ are each optionallysubstituted with 1, 2, 3, or 4 R^(b) substituents;

or two adjacent R⁷ substituents on the Cy ring, taken together with theatoms to which they are attached, form a fused phenyl ring, a fused 5-,6- or 7-membered heterocycloalkyl ring, a fused 5- or 6-memberedheteroaryl ring or a fused C₃₋₆ cycloalkyl ring, wherein the fused 5-,6- or 7-membered heterocycloalkyl ring and fused 5- or 6-memberedheteroaryl ring each have 1-4 heteroatoms as ring members selected fromN, O and S and wherein the fused phenyl ring, fused 5-, 6- or 7-memberedheterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fusedC₃₋₆ cycloalkyl ring are each optionally substituted with 1, 2 or 3independently selected R^(b) substituents;

or two R¹³ substituents attached to the same carbon atom, taken togetherwith the carbon atom to which they are attached, form a C₃₋₆ cycloalkylring or 4-, 5-, 6- or 7-membered heterocycloalkyl ring, wherein the C₃₋₆cycloalkyl ring and 4-, 5-, 6- or 7-membered heterocycloalkyl ring areeach optionally substituted with 1, 2 or 3 independently selected R^(b)substituents;

each R^(a) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(a) are each optionally substitutedwith 1, 2, 3, 4, or 5 R^(d) substituents;

each R^(d) is independently selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl,halo, C₃₋₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, CN, NH₂,NHOR^(e), OR^(e), SR^(e), C(O)R^(e), C(O)NR^(e)R^(e), C(O)OR^(e),OC(O)R^(e), OC(O)NR^(e)R^(e), NHR^(e), NR^(e)R^(e), NR^(e)C(O)R^(e),NR^(e)C(O)NR^(e)R^(e), NR^(e)C(O)OR^(e), C(═NR^(e))NR^(e)R^(e),NR^(e)C(═NR^(e))NR^(e)R^(e), S(O)R^(e), S(O)NR^(e)R^(e), S(O)₂R^(e),NR^(e)S(O)₂R^(e), NR^(e)S(O)₂NR^(e)R^(e), and S(O)₂NR^(e)R^(e), where inthe C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl and 4-10 membered heterocycloalkyl ofR^(d) are each further optionally substituted with 1-3 independentlyselected R^(q) substituents;

each R^(b) substituent is independently selected from halo, C₁₋₄ alkyl,C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, CN, OH, NH₂, NO₂,NHOR^(c), OR^(c), SR^(c), C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c),OC(O)R^(c), OC(O)NR^(c)R^(c), C(═NR^(c))NR^(c)R^(c),NR^(c)C(═NR^(c))NR^(c)R^(c), NHR^(c), NR^(c)R^(c), NR^(c)C(O)R^(c),NR^(c)C(O)OR^(c), NR^(c)C(O)NR^(c)R^(c), NR^(c)S(O)R^(c),NR^(c)S(O)₂R^(c), NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c), S(O)NR^(c)R^(c),S(O)₂R^(c) and S(O)₂NR^(c)R^(c); wherein the C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₁₋₄ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(b) are each furtheroptionally substituted with 1-3 independently selected R^(d)substituents;

each R^(c) is independently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(c) areeach optionally substituted with 1, 2, 3, 4, or 5 R^(f) substituentsindependently selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10membered heterocycloalkyl)-C₁₋₄ alkyl-, halo, CN, NHOR^(g), OR^(g),SR^(g), C(O)R^(g), C(O)NR^(g)R^(g), C(O)OR^(g), OC(O)R^(g),OC(O)NR^(g)R^(g), NHR^(g), NR^(g)R^(g), NR^(g)C(O)R^(g),NR^(g)C(O)NR^(g)R^(g), NR^(g)C(O)OR^(g), C(═NR^(g))NR^(g)R^(g),NR^(g)C(═NR^(g))NR^(g)R^(g), S(O)R^(g), S(O)NR^(g)R^(g), S(O)₂R^(g),NR^(g)S(O)₂R^(g), NR^(g)S(O)₂NR^(g)R^(g), and S(O)₂NR^(g)R^(g); whereinthe C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(f) are each optionally substitutedwith 1, 2, 3, 4, or 5 R^(n) substituents independently selected fromC₁₋₄ alkyl, C₁₋₄ haloalkyl, halo, CN, NHOR^(o), OR^(o), SR^(o),C(O)R^(o), C(O)NR^(o)R^(o), C(O)OR^(o), OC(O)R^(o), OC(O)NR^(o)R^(o),NHR^(o), NR^(o)R^(o), NR^(o)C(O)R^(o), NR^(o)C(O)NR^(o)R^(o),NR^(o)C(O)OR^(o), C(═NR^(o))NR^(o)R^(o), NR^(o)C(═NR^(o))NR^(o)R^(o),S(O)R^(o), S(O)NR^(o)R^(o), S(O)₂R^(o), NR^(o)S(O)₂R^(o),NR^(o)S(O)₂NR^(o)R^(o), and S(O)₂NR^(o)R^(o);

each R^(g) is independently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(g) areeach optionally substituted with 1-3 independently selected R^(p)substituents;

or any two R^(a) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-memberedheterocycloalkyl group optionally substituted with 1, 2 or 3 R^(h)substituents independently selected from C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl,4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-6 membered heteroaryl)-C₁₋₄ alkyl-,(4-7 membered heterocycloalkyl)-C₁₋₄ alkyl-, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, halo, CN, OR^(i), SR^(i), NHOR^(i), C(O)R^(i),C(O)NR^(i)R^(i), C(O)OR^(i), OC(O)R^(i), OC(O)NR^(i)R^(i), NHR^(i),NR^(i)R^(i), NR^(i)C(O)R^(i), NR^(i)C(O)NR^(i)R^(i), NR^(i)C(O)OR^(i),C(═NR^(i))NR^(i)R^(i), NR^(i)C(═NR^(i))NR^(i)R^(i), S(O)R^(i),S(O)NR^(i)R^(i), S(O)₂R^(i), NR^(i)S(O)₂R^(i), NR^(i)S(O)₂NR^(i)R^(i),and S(O)₂NR^(i)R^(i), wherein the C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, 4-7membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-6 membered heteroaryl)-C₁₋₄ alkyl-, (4-7membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(h) are each furtheroptionally substituted by 1, 2, or 3 substituents independently selectedfrom C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, C₂₋₄alkenyl, C₂₋₄ alkynyl, halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, CN, NHOR^(k),OR^(k), SR^(k), C(O)R^(k), C(O)NR^(k)R^(k), C(O)OR^(k), OC(O)R^(k),OC(O)NR^(k)R^(k), NHR^(k), NR^(k)R^(k), NR^(k)C(O)R^(k),NR^(k)C(O)NR^(k)R^(k), NR^(k)C(O)OR^(k), C(═NR^(k))NR^(k)R^(k),NR^(k)C(═NR^(k))NR^(k)R^(k), S(O)R^(k), S(O)NR^(k)R^(k), S(O)₂R^(k),NR^(k)S(O)₂R^(k), NR^(k)S(O)₂NR^(k)R^(k), and S(O)₂NR^(k)R^(k);

or two R^(h) groups attached to the same carbon atom of the 4- to10-membered heterocycloalkyl taken together with the carbon atom towhich they are attached form a C₃₋₆ cycloalkyl or 4- to 6-memberedheterocycloalkyl having 1-2 heteroatoms as ring members selected from O,N or S;

or any two R^(c) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(e) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(g) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(i) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(k) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents;

or any two R^(o) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents; and

each R^(e), R^(i), R^(k), R^(o) or R^(p) is independently selected fromH, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-membered heteroaryl,C₁₋₄ haloalkyl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl, wherein the C₁₋₄ alkyl,C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-membered heteroaryl, C₂₋₄ alkenyl,and C₂₋₄ alkynyl of R^(e), R^(i), R^(k), R^(o) or R^(p) are eachoptionally substituted with 1, 2 or 3 R^(q) substituents;

each R^(q) is independently selected from OH, CN, —COOH, NH₂, halo,C₁₋₆haloalkyl, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₆ alkylthio,phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, C₃₋₆cycloalkyl, NHR¹², NR¹²R¹², and C₁₋₄ haloalkoxy, wherein the C₁₋₆ alkyl,phenyl, C₃₋₆ cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 memberedheteroaryl of R^(q) are each optionally substituted with halo, OH, CN,—COOH, NH₂, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, phenyl, C₃₋₁₀cycloalkyl and 4-6 membered heterocycloalkyl and each R¹² isindependently C₁₋₆ alkyl;

is a single bond or a double bond to maintain ring A being aromatic;

the subscript n is an integer of 1, 2, 3, 4, 5 or 6; and

when R⁹ is OH, Cy is other than6-carbamimidoyl-1H-benzo[d]imidazol-2-yl.

The compounds, or pharmaceutically acceptable salts or stereoisomersthereof, as described herein are useful as inhibitors of the PD-1/PD-L1protein/protein interaction. For example, compounds or pharmaceuticallyacceptable salts or stereoisomers thereof as described herein candisrupt the PD-1/PD-L1 protein/protein interaction in the PD-1 pathway.

In some embodiments of compounds of Formula (I), when R⁹ is OH, Cy isother than 1H-benzo[d]imidazol-2-yl optionally substituted with a R⁷substituent.

In some embodiments of compounds of Formula (I), R⁷, R¹³ and R¹⁴ areeach independently selected from H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-14 memberedheteroaryl)-C₁₋₄ alkyl-, (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-,CN, NO₂, OR^(a), SR^(a), NHOR^(a), C(O)R^(a), C(O)NR^(a)R^(a),C(O)OR^(a), OC(O)R^(a), OC(O)NR^(a)R^(a), NHR^(a), NR^(a)R^(a),NR^(a)C(O)R^(a), NR^(a)C(O)OR^(a), NR^(a)C(O)NR^(a)R^(a),C(═NR^(a))R^(a), C(═NR^(a))NR^(a)R^(a), NR^(a)C(═NR^(a))NR^(a)R^(a),NR^(a)S(O)R^(a), NR^(a)S(O)₂R^(a), NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a),S(O)NR^(a)R^(a), S(O)₂R^(a), and S(O)₂NR^(a)R^(a), where in the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-14 membered heteroaryl)-C₁₋₄alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R⁷, R¹³ andR¹⁴ are each optionally substituted with 1, 2, 3, or 4 R^(q)substituents.

In some embodiments of compounds of Formula (I), two adjacent R⁷substituents on the Cy ring, taken together with the atoms to which theyare attached, form a fused phenyl ring, a fused 5-, 6- or 7-memberedheterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or afused C₃₋₆ cycloalkyl ring, wherein the fused 5-, 6- or 7-memberedheterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring eachhave 1-4 heteroatoms as ring members selected from N, O and S andwherein the fused phenyl ring, fused 5-, 6- or 7-memberedheterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fusedC₃₋₆ cycloalkyl ring are each optionally substituted with 1, 2 or 3independently selected R^(q) substituents.

In some embodiments of compounds of Formula (I), Cy is C₆₋₁₀ aryl,optionally substituted with 1 to 5 independently selected R⁷substituents. In certain embodiments, Cy is phenyl or naphthyl, each ofwhich is optionally substituted with 1 to 4 independently selected R⁷substituents. In certain embodiments, Cy is phenyl optionallysubstituted with 1 to 5 independently selected R⁷ substituents. Incertain embodiments, Cy is unsubstituted phenyl. In certain embodiments,Cy is 2,3-dihydro-1,4-benzodioxin-6-yl, optionally substituted with 1 to5 independently selected R⁷ substituents.

In some embodiments of compounds of Formula (I), Cy is C₃₋₁₀ cycloalkyl,optionally substituted with 1 to 5 independently selected R⁷substituents. In certain embodiments, Cy is cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl or cyclooctyl, eachof which is optionally substituted with 1 to 5 independently selected R⁷substituents.

In some embodiments of compounds of Formula (I), Cy is 5- to 14-memberedheteroaryl, optionally substituted with 1 to 5 independently selected R⁷substituents. In certain embodiments, Cy is pyridyl, primidinyl,pyrazinyl, pyridazinyl, triazinyl, pyrrolyl, pyrazolyl, azolyl,oxazolyl, thiazolyl, imidazolyl, furanyl, thiophenyl, quinolinyl,isoquinolinyl, naphthyridinyl, indolyl, benzothiophenyl, benzofuranyl,benzisoxazolyl, imidazo[1,2-b]thiazolyl, purinyl, thienyl, furyl,pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl,isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl,1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl,1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl and1,3,4-oxadiazolyl, each of which is optionally substituted with 1 to 5independently selected R⁷ substituents. In certain embodiments, Cy isthiophenyl or pyridyl, each of which is optionally substituted with 1 to5 independently selected R⁷ substituents. In some embodiments, Cy is2-thiophenyl, 3-thiophenyl, 2-pyridyl, 3-pyridyl or 4-pyridyl, each ofwhich is optionally substituted with 1 to 5 independently selected R⁷substituents.

In some embodiments of compounds of Formula (I), Cy is 4- to 10-memberedheterocycloalkyl, optionally substituted with 1 to 5 independentlyselected R⁷ substituents. In certain embodiments, Cy is azetidinyl,azepanyl, dihydrobenzofuranyl, dihydrofuranyl, dihydropyranyl,morpholino, 3-oxa-9-azaspiro[5.5]undecanyl,1-oxa-8-azaspiro[4.5]decanyl, piperidinyl, piperazinyl, oxopiperazinyl,pyranyl, pyrrolidinyl, quinuclidinyl, tetrahydrofuranyl,tetrahydropyranyl, 1,2,3,4-tetrahydroquinolinyl, tropanyl,2,3-dihydro-1,4-benzodioxin-6-yl, and thiomorpholino, each of which isoptionally substituted with 1 to 4 independently selected R⁷substituents. In some embodiments, Cy is 3,6-dihydro-2H-pyran-4-yl,optionally substituted with 1 to 5 independently selected R⁷substituents.

In some embodiments of compounds of Formula (I), Cy is phenyl, 5- or6-membered heteroaryl, C₃₋₆ cycloalkyl or 5- or 6-memberedheterocycloalkyl, each of which is optionally substituted with 1 to 5independently selected R⁷ substituents. In certain instances, Cy isphenyl, 2-thiophenyl, 3-thiophenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,C₃₋₆ cycloalkyl or 3,6-dihydro-2H-pyran-4-yl, each of which isoptionally substituted with 1 to 5 R⁷ substituents.

In some embodiments of compounds of Formula (I), X⁴ is CR⁴, X⁵ is CR⁵and X⁶ is CR⁶. In certain instances, R⁴, R⁵ and R⁶ are each H.

In some embodiments of compounds of Formula (I), X⁴ is CR⁴, X⁵ is N andX⁶ is N. In certain instances, R⁴ is H.

In some embodiments of compounds of Formula (I), X⁴ is CR⁴, X⁵ is N andX⁶ is CR⁶. In certain instances, R⁴ and R⁶ are each H.

In some embodiments of compounds of Formula (I), X⁴ is CR⁴, X⁵ is CR⁵and X⁶ is N. In certain instances, R⁴ and R⁵ are each H.

In some embodiments of compounds of Formula (I), X⁴ is N, X⁵ is CR⁵ andX⁶ is CR⁶. In certain instances, R⁵ and R⁶ are each H.

In some embodiments of compounds of Formula (I), X⁴ is N, X⁵ is N and X⁶is CR⁶. In certain instances, R⁶ is H.

In some embodiments of compounds of Formula (I), X⁴ is N, X⁵ is CR⁵ andX⁶ is N. In certain instances, R⁵ is H.

In some embodiments, the present disclosure provides compounds havingFormula (II):

or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinthe variables of Formula (II) are as defined in Formula (I) or anyembodiment of compounds of Formula (I) as described herein. In oneembodiment of compounds of Formula (II), R⁹ is halo, CN or C₁₋₄ alkyloptionally substituted with 1 or 2 R^(q) groups. In another embodiment,R⁹ is Cl, CH₃ or CN.

In some embodiments, the present disclosure provides compounds havingFormula (IIa):

or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinthe variables of Formula (IIa) are as defined in Formula (I) or anyembodiment of compounds of Formula (I) as described herein. In oneembodiment, Cy is phenyl optionally substituted with 1 to 5 R⁷ groups.In one embodiment, R⁹ is halo, CN or C₁₋₄ alkyl optionally substitutedwith 1 or 2 R^(q) groups. In another embodiment, R⁹ is Cl, CH₃ or CN.

In some embodiments, the present disclosure provides compounds havingFormula (III):

or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinthe variables of Formula (III) are as defined in Formula (I) or anyembodiment of compounds of Formula (I) as described herein. In oneembodiment, Cy is phenyl optionally substituted with 1 to 5 R⁷ groups.In one embodiment, R⁵ and Ware H. In one embodiment, R⁹ is halo, CN orC₁₋₄ alkyl optionally substituted with 1 or 2 R^(q) groups. In anotherembodiment, R⁹ is Cl, CH₃ or CN.

In some embodiments, the present disclosure provides compounds havingFormula (IV):

or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinthe variables of Formula (IV) are as defined in Formula (I) or anyembodiment of compounds of Formula (I) as described herein. In oneembodiment, Cy is phenyl optionally substituted with 1 to 5 R⁷ groups.In one embodiment, R⁴ and R⁵ are H. In one embodiment, R⁹ is halo, CN orC₁₋₄ alkyl optionally substituted with 1 or 2 R^(q) groups. In anotherembodiment, R⁹ is Cl, CH₃ or CN.

In some embodiments, the present disclosure provides compounds havingFormula (V):

or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinthe variables of Formula (V) are as defined in Formula (I) or anyembodiment of compounds of Formula (I) as described herein. In oneembodiment, R⁹ is halo, CN or C₁₋₄ alkyl optionally substituted with 1or 2 R^(q) groups. In another embodiment, R⁹ is Cl, CH₃ or CN.

In some embodiments, the present disclosure provides compounds havingFormula (VI):

or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinthe subscript m is an integer of 1, 2, 3 or 4 and the variables ofFormula (VI) are as defined in Formula (I) or any embodiment ofcompounds of Formula (I) as described herein. The moiety

in Formula (VI) is

In certain embodiments, the present disclosure provides compounds havingFormula (VIa):

or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinthe subscript m is an integer of 1, 2, 3 or 4 and the variables ofFormula (VIa) are as defined in Formula (I) or any embodiment ofcompounds of Formula (I) as described herein.

In certain embodiments, the present disclosure provides compounds havingFormula (VIb):

or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinthe subscript m is an integer of 1, 2, 3 or 4 and the variables ofFormula (VIb) are as defined in Formula (I) or any embodiment ofcompounds of Formula (I) as described herein.

In certain embodiments, the present disclosure provides compounds havingFormula (VIc):

or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinthe subscript m is an integer of 1, 2, 3 or 4 and the variables ofFormula (VIc) are as defined in Formula (I) or any embodiment ofcompounds of Formula (I) as described herein.

In some embodiments, the present disclosure provides compounds havingFormula (VII):

or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinm is an integer of 1, 2 or 3 and the variables of Formula (VII) are asdefined in Formula (I) or any embodiment of compounds of Formula (I) asdescribed herein. The moiety

in Formula (VII) is

In some embodiments, the present disclosure provides compounds havingFormula (VIIa):

or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinm is an integer of 1, 2 or 3 and the variables of Formula (VIIa) are asdefined in Formula (I) or any embodiment of compounds of Formula (I) asdescribed herein.

In some embodiments, the present disclosure provides compounds havingFormula (VIIb):

or a pharmaceutically acceptable salt or a stereoisomer thereof, whereinm is an integer of 1, 2 or 3 and the variables of Formula (VIIb) are asdefined in Formula (I) or any embodiment of compounds of Formula (I) asdescribed herein.

In some embodiments of compounds of any of the Formulas as disclosedherein or a pharmaceutically acceptable salt or a stereoisomer thereof,the moiety:

is selected from:

wherein the substituents R¹, R³, R¹³, R¹⁴ and the subscript n are asdefined in Formula (I) or any embodiment of compounds of Formula (I) asdescribed herein. In certain embodiments, at each occurrence, R¹ and R³are each H. In other embodiments, R¹³ is H or C₁₋₆ alkyl. In oneembodiment, the subscript n is 2.

In some embodiments of compounds of any of the Formula as disclosedherein or a pharmaceutically acceptable salt or a stereoisomer thereof,the moiety:

is selected from:

In some embodiments of compounds of any of the Formulas as disclosedherein, X¹ is N, X² is C, X³ is S and Y is C. In some instances, X⁴, X⁵and X⁶ are each CH.

In some embodiments of compounds of any of the Formulas as disclosedherein, X¹ is S, X² is C, X³ is N, and Y is C. In some instances, X⁴, X⁵and X⁶ are each CH.

In some embodiments of compounds of any of the Formulas as disclosedherein, X¹ is N, X² is C, X³ is CR³, and Y is N. In some instances, X⁴,X⁵ and X⁶ are each CH.

In some embodiments of compounds of any of the Formulas as disclosedherein, X¹ is N, X² is C, X³ is NR³, and Y is C. In some instances, X⁴,X⁵ and X⁶ are each CH.

In some embodiments of compounds of any of the Formulas as disclosedherein, X¹ is N, X² is C, X³ is S, X⁶ is N, and Y is C. In someinstances, X⁴ and X⁵ are each CH.

In some embodiments of compounds of any of the Formulas as disclosedherein, X¹ is N, X² is N, X³ is CR³, and Y is C. In some instances, X⁴,X⁵ and X⁶ are each CH.

In some embodiments of compounds of any of the Formulas as disclosedherein, X¹ is CR¹, X² is N, X³ is N, and Y is C. In some instances, X⁴,X⁵ and X⁶ are each CH.

In some embodiments of compounds of any of the Formulas as disclosedherein, X¹ is CR¹, X² is C, X³ is N, and Y is N. In some instances, X⁴,X⁵ and X⁶ are each CH.

In some embodiments of compounds of any of the Formulas as disclosedherein, X¹ is NR¹, X² is C, X³ is N, and Y is C. In some instances, X⁴,X⁵ and X⁶ are each CH.

In some embodiments of compounds of any of the Formulas as disclosedherein, X¹ is N, X² is C, X³ is O, and Y is C. In some instances, X⁴, X⁵and X⁶ are each CH.

In some embodiments of compounds of any of the Formulas as disclosedherein, X¹ is O, X² is C, X³ is N, and Y is C. In some instances, X⁴, X⁵and X⁶ are each CH.

In some embodiments of compounds of any of the Formulas as disclosedherein, X¹ is N, X² is C, X³ is N, and Y is N. In some instances, X⁴, X⁵and X⁶ are each CH.

In some embodiments of compounds of any of the Formulas as disclosedherein, X¹ is N, X² is C, X³ is S, X⁴ is N, and Y is C. In someinstances, X⁵ and X⁶ are each CH.

In some embodiments, R¹, R³, R⁴, R⁵ and R⁶ are each H.

In some embodiments, R⁹ is halo, C₁₋₄ alkyl or CN.

In some embodiments, R⁹ is CH₃ or CN. In certain embodiments, R⁹ is Cl,CH₃ or CN. In one embodiment, R⁹ is CH₃. In another embodiment, R⁹ isCN. In another embodiment, R⁹ is F, Cl or Br.

In some embodiments, R⁷ is H.

In some embodiments, R⁴, R⁵ and R⁶ are each H.

In some embodiments of compounds of any of the Formulas as disclosedherein, R¹³ is H or C₁₋₆ alkyl.

In some embodiments of compounds of any of the Formulas as disclosedherein, two R¹³ substituents attached to the same carbon atom, takentogether with the carbon atom to which they are attached, form a C₃₋₆cycloalkyl ring or 4-, 5-, 6- or 7-membered heterocycloalkyl ring,wherein the C₃₋₆ cycloalkyl ring and 4-, 5-, 6- or 7-memberedheterocycloalkyl ring are each optionally substituted with 1, 2 or 3independently selected R^(q) substituents. Exemplary spiro C₃₋₆cycloalkyl ring formed by two R¹³ substituents include cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl.

In some embodiments of compounds of any of the Formulas as disclosedherein, R¹⁴ is H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-14 membered heteroaryl)-C₁₋₄ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a), SR^(a),NHOR^(a), C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a),OC(O)NR^(a)R^(a), NHR^(a), NR^(a)R^(a), NR^(a)C(O)R^(a),NR^(a)C(O)OR^(a), NR^(a)C(O)NR^(a)R^(a), C(═NR^(a))R^(a),C(═NR^(a))NR^(a)R^(a), NR^(a)C(═NR^(a))NR^(a)R^(a), NR^(a)S(O)R^(a),NR^(a)S(O)₂R^(a), NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a),S(O)₂R^(a), and S(O)₂NR^(a)R^(a), where in the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-14 membered heteroaryl)-C₁₋₄ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R¹⁴ are each optionallysubstituted with 1, 2, 3, or 4 R^(b) substituents or 1, 2, 3 or 4 R^(q)substituents.

In some embodiments of compounds of any of the Formulas as disclosedherein, R¹⁴ is H, C₁₋₆ alkyl, phenyl, phenyl-C₁₋₄ alkyl-, C₃₋₆cycloalkyl, C₃₋₆ cycloalkyl-C₁₋₄ alkyl-, 5- or 6-membered heteroaryl, 4-to 6-membered heterocycloalkyl, (5- or 6-membered heteroaryl)-C₁₋₄alkyl- or (4- to 6-membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein theC₁₋₆ alkyl, phenyl, phenyl-C₁₋₄ alkyl-, C₃₋₆ cycloalkyl, C₃₋₆cycloalkyl-C₁₋₄ alkyl-, 5- or 6-membered heteroaryl, 4- to 6-memberedheterocycloalkyl, (5- or 6-membered heteroaryl)-C₁₋₄ alkyl- or (4- to6-membered heterocycloalkyl)-C₁₋₄ alkyl- of R¹⁴ is optionallysubstituted with 1, 2, 3 or 4 R^(q) substituents.

In some embodiments of compounds of any of the Formulas as disclosedherein, R¹⁴ is 2-hydroxyethyl, 2-hydroxypropyl, (R)-2-hydroxypropyl,(S)-2-hydroxypropyl, tetrahydro-2H-pyran-4-yl, 4-carboxycyclohexyl,3-carboxypropyl, 2-carboxycyclopropylmethyl, 1H-pyrazol-4-ylmethyl or4-cyanomethylcyclohexyl.

It is further appreciated that certain features of the invention, whichare, for clarity, described in the context of separate embodiments, canalso be provided in combination in a single embodiment (while theembodiments are intended to be combined as if written in multiplydependent form). Conversely, various features of the invention whichare, for brevity, described in the context of a single embodiment, canalso be provided separately or in any suitable subcombination. Thus, itis contemplated as features described as embodiments of the compounds ofFormula (I) can be combined in any suitable combination.

At various places in the present specification, certain features of thecompounds are disclosed in groups or in ranges. It is specificallyintended that such a disclosure include each and every individualsubcombination of the members of such groups and ranges. For example,the term “C₁₋₆ alkyl” is specifically intended to individually disclose(without limitation) methyl, ethyl, C₃ alkyl, C₄ alkyl, C₅ alkyl and C₆alkyl.

The term “n-membered,” where n is an integer, typically describes thenumber of ring-forming atoms in a moiety where the number ofring-forming atoms is n. For example, piperidinyl is an example of a6-membered heterocycloalkyl ring, pyrazolyl is an example of a5-membered heteroaryl ring, pyridyl is an example of a 6-memberedheteroaryl ring and 1,2,3,4-tetrahydro-naphthalene is an example of a10-membered cycloalkyl group.

At various places in the present specification, variables definingdivalent linking groups may be described. It is specifically intendedthat each linking substituent include both the forward and backwardforms of the linking substituent. For example, —NR(CR′R″)_(n)-includesboth —NR(CR′R″)_(n)— and —(CR′R″)_(n)NR— and is intended to discloseeach of the forms individually. Where the structure requires a linkinggroup, the Markush variables listed for that group are understood to belinking groups. For example, if the structure requires a linking groupand the Markush group definition for that variable lists “alkyl” or“aryl” then it is understood that the “alkyl” or “aryl” represents alinking alkylene group or arylene group, respectively.

The term “substituted” means that an atom or group of atoms formallyreplaces hydrogen as a “substituent” attached to another group. The term“substituted”, unless otherwise indicated, refers to any level ofsubstitution, e.g., mono-, di-, tri-, tetra- or penta-substitution,where such substitution is permitted. The substituents are independentlyselected, and substitution may be at any chemically accessible position.It is to be understood that substitution at a given atom is limited byvalency. It is to be understood that substitution at a given atomresults in a chemically stable molecule. The phrase “optionallysubstituted” means unsubstituted or substituted. The term “substituted”means that a hydrogen atom is removed and replaced by a substituent. Asingle divalent substituent, e.g., oxo, can replace two hydrogen atoms.

The term “C_(n-m)” indicates a range which includes the endpoints,wherein n and m are integers and indicate the number of carbons.Examples include C₁₋₄, C₁₋₆ and the like.

The term “alkyl” employed alone or in combination with other terms,refers to a saturated hydrocarbon group that may be straight-chained orbranched. The term “C_(n-m) alkyl”, refers to an alkyl group having n tom carbon atoms. An alkyl group formally corresponds to an alkane withone C—H bond replaced by the point of attachment of the alkyl group tothe remainder of the compound. In some embodiments, the alkyl groupcontains from 1 to 6 carbon atoms, from 1 to 4 carbon atoms, from 1 to 3carbon atoms, or 1 to 2 carbon atoms. Examples of alkyl moietiesinclude, but are not limited to, chemical groups such as methyl, ethyl,n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; higherhomologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl,1,2,2-trimethylpropyl and the like.

The term “alkenyl” employed alone or in combination with other terms,refers to a straight-chain or branched hydrocarbon group correspondingto an alkyl group having one or more double carbon-carbon bonds. Analkenyl group formally corresponds to an alkene with one C—H bondreplaced by the point of attachment of the alkenyl group to theremainder of the compound. The term “C_(n-m) alkenyl” refers to analkenyl group having n to m carbons. In some embodiments, the alkenylmoiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. Example alkenylgroups include, but are not limited to, ethenyl, n-propenyl,isopropenyl, n-butenyl, sec-butenyl and the like.

The term “alkynyl” employed alone or in combination with other terms,refers to a straight-chain or branched hydrocarbon group correspondingto an alkyl group having one or more triple carbon-carbon bonds. Analkynyl group formally corresponds to an alkyne with one C—H bondreplaced by the point of attachment of the alkyl group to the remainderof the compound. The term “C_(n-m) alkynyl” refers to an alkynyl grouphaving n to m carbons. Example alkynyl groups include, but are notlimited to, ethynyl, propyn-1-yl, propyn-2-yl and the like. In someembodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3carbon atoms.

The term “alkylene”, employed alone or in combination with other terms,refers to a divalent alkyl linking group. An alkylene group formallycorresponds to an alkane with two C—H bond replaced by points ofattachment of the alkylene group to the remainder of the compound. Theterm “C_(n-m) alkylene” refers to an alkylene group having n to m carbonatoms. Examples of alkylene groups include, but are not limited to,ethan-1,2-diyl, propan-1,3-diyl, propan-1,2-diyl, butan-1,4-diyl,butan-1,3-diyl, butan-1,2-diyl, 2-methyl-propan-1,3-diyl and the like.

The term “alkoxy”, employed alone or in combination with other terms,refers to a group of formula —O-alkyl, wherein the alkyl group is asdefined above. The term “C_(n-m) alkoxy” refers to an alkoxy group, thealkyl group of which has n to m carbons. Example alkoxy groups includemethoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy andthe like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1to 3 carbon atoms.

The term “amino” refers to a group of formula —NH₂.

The term “carbonyl”, employed alone or in combination with other terms,refers to a —C(═O)— group, which also may be written as C(O).

The term “cyano” or “nitrile” refers to a group of formula —C≡N, whichalso may be written as —CN.

The terms “halo” or “halogen”, used alone or in combination with otherterms, refers to fluoro, chloro, bromo and iodo. In some embodiments,“halo” refers to a halogen atom selected from F, Cl, or Br. In someembodiments, halo groups are F.

The term “haloalkyl” as used herein refers to an alkyl group in whichone or more of the hydrogen atoms has been replaced by a halogen atom.The term “C_(n-m) haloalkyl” refers to a C_(n-m) alkyl group having n tom carbon atoms and from at least one up to {2(n to m)+1} halogen atoms,which may either be the same or different. In some embodiments, thehalogen atoms are fluoro atoms. In some embodiments, the haloalkyl grouphas 1 to 6 or 1 to 4 carbon atoms. Example haloalkyl groups include CF₃,C₂F₅, CHF₂, CCl₃, CHCl₂, C₂Cl₅ and the like. In some embodiments, thehaloalkyl group is a fluoroalkyl group.

The term “haloalkoxy”, employed alone or in combination with otherterms, refers to a group of formula —O-haloalkyl, wherein the haloalkylgroup is as defined above. The term “C_(n-m) haloalkoxy” refers to ahaloalkoxy group, the haloalkyl group of which has n to m carbons.Example haloalkoxy groups include trifluoromethoxy and the like. In someembodiments, the haloalkoxy group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

The term “oxo” refers to an oxygen atom as a divalent substituent,forming a carbonyl group when attached to carbon, or attached to aheteroatom forming a sulfoxide or sulfone group, or an N-oxide group. Insome embodiments, heterocyclic groups may be optionally substituted by 1or 2 oxo (═O) substituents.

The term “sulfido” refers to a sulfur atom as a divalent substituent,forming a thiocarbonyl group (C═S) when attached to carbon.

The term “aromatic” refers to a carbocycle or heterocycle having one ormore polyunsaturated rings having aromatic character (i.e., having(4n+2) delocalized π (pi) electrons where n is an integer).

The term “aryl,” employed alone or in combination with other terms,refers to an aromatic hydrocarbon group, which may be monocyclic orpolycyclic (e.g., having 2 fused rings). The term “C_(n-m) aryl” refersto an aryl group having from n to m ring carbon atoms. Aryl groupsinclude, e.g., phenyl, naphthyl, indanyl, indenyl and the like. In someembodiments, aryl groups have from 6 to about 10 carbon atoms. In someembodiments aryl groups have 6 carbon atoms. In some embodiments arylgroups have 10 carbon atoms. In some embodiments, the aryl group isphenyl. In some embodiments, the aryl group is naphthyl.

The term “heteroaryl” or “heteroaromatic,” employed alone or incombination with other terms, refers to a monocyclic or polycyclicaromatic heterocycle having at least one heteroatom ring member selectedfrom sulfur, oxygen and nitrogen. In some embodiments, the heteroarylring has 1, 2, 3 or 4 heteroatom ring members independently selectedfrom nitrogen, sulfur and oxygen. In some embodiments, any ring-formingN in a heteroaryl moiety can be an N-oxide. In some embodiments, theheteroaryl has 5-14 ring atoms including carbon atoms and 1, 2, 3 or 4heteroatom ring members independently selected from nitrogen, sulfur andoxygen. In some embodiments, the heteroaryl has 5-10 ring atomsincluding carbon atoms and 1, 2, 3 or 4 heteroatom ring membersindependently selected from nitrogen, sulfur and oxygen. In someembodiments, the heteroaryl has 5-6 ring atoms and 1 or 2 heteroatomring members independently selected from nitrogen, sulfur and oxygen. Insome embodiments, the heteroaryl is a five-membered or six-memberedheteroaryl ring. In other embodiments, the heteroaryl is aneight-membered, nine-membered or ten-membered fused bicyclic heteroarylring. Example heteroaryl groups include, but are not limited to,pyridintl (pyridyl), pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl,pyrazolyl, azolyl, oxazolyl, thiazolyl, imidazolyl, furanyl, thiophenyl,quinolinyl, isoquinolinyl, naphthyridinyl (including 1,2-, 1,3-, 1,4-,1,5-, 1,6-, 1,7-, 1,8-, 2,3- and 2,6-naphthyridine), indolyl,benzothiophenyl, benzofuranyl, benzisoxazolyl, imidazo[1,2-b]thiazolyl,purinyl, and the like.

A five-membered heteroaryl ring is a heteroaryl group having five ringatoms wherein one or more (e.g., 1, 2 or 3) ring atoms are independentlyselected from N, O and S. Exemplary five-membered ring heteroarylsinclude thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl,pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl,1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl,1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl,1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl.

A six-membered heteroaryl ring is a heteroaryl group having six ringatoms wherein one or more (e.g., 1, 2 or 3) ring atoms are independentlyselected from N, O and S. Exemplary six-membered ring heteroaryls arepyridyl, pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl.

The term “cycloalkyl,” employed alone or in combination with otherterms, refers to a non-aromatic hydrocarbon ring system (monocyclic,bicyclic or polycyclic), including cyclized alkyl and alkenyl groups.The term “C_(n-m) cycloalkyl” refers to a cycloalkyl that has n to mring member carbon atoms. Cycloalkyl groups can include mono- orpolycyclic (e.g., having 2, 3 or 4 fused rings) groups and spirocycles.Cycloalkyl groups can have 3, 4, 5, 6 or 7 ring-forming carbons (C₃₋₇).In some embodiments, the cycloalkyl group has 3 to 6 ring members, 3 to5 ring members, or 3 to 4 ring members. In some embodiments, thecycloalkyl group is monocyclic. In some embodiments, the cycloalkylgroup is monocyclic or bicyclic. In some embodiments, the cycloalkylgroup is a C₃₋₆ monocyclic cycloalkyl group. Ring-forming carbon atomsof a cycloalkyl group can be optionally oxidized to form an oxo orsulfido group. Cycloalkyl groups also include cycloalkylidenes. In someembodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl. Also included in the definition of cycloalkyl are moietiesthat have one or more aromatic rings fused (i.e., having a bond incommon with) to the cycloalkyl ring, e.g., benzo or thienyl derivativesof cyclopentane, cyclohexane and the like. A cycloalkyl group containinga fused aromatic ring can be attached through any ring-forming atomincluding a ring-forming atom of the fused aromatic ring. Examples ofcycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl,cycloheptatrienyl, norbornyl, norpinyl, norcarnyl,bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, and the like. In someembodiments, the cycloalkyl group is cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl.

The term “heterocycloalkyl,” employed alone or in combination with otherterms, refers to a non-aromatic ring or ring system, which mayoptionally contain one or more alkenylene groups as part of the ringstructure, which has at least one heteroatom ring member independentlyselected from nitrogen, sulfur oxygen and phosphorus, and which has 4-10ring members, 4-7 ring members, or 4-6 ring members. Included within theterm “heterocycloalkyl” are monocyclic 4-, 5-, 6- and 7-memberedheterocycloalkyl groups. Heterocycloalkyl groups can include mono- orbicyclic (e.g., having two fused or bridged rings) ring systems. In someembodiments, the heterocycloalkyl group is a monocyclic group having 1,2 or 3 heteroatoms independently selected from nitrogen, sulfur andoxygen. Ring-forming carbon atoms and heteroatoms of a heterocycloalkylgroup can be optionally oxidized to form an oxo or sulfido group orother oxidized linkage (e.g., C(O), S(O), C(S) or S(O)₂, N-oxide etc.)or a nitrogen atom can be quaternized. The heterocycloalkyl group can beattached through a ring-forming carbon atom or a ring-formingheteroatom. In some embodiments, the heterocycloalkyl group contains 0to 3 double bonds. In some embodiments, the heterocycloalkyl groupcontains 0 to 2 double bonds. Also included in the definition ofheterocycloalkyl are moieties that have one or more aromatic rings fused(i.e., having a bond in common with) to the heterocycloalkyl ring, e.g.,benzo or thienyl derivatives of piperidine, morpholine, azepine, etc. Aheterocycloalkyl group containing a fused aromatic ring can be attachedthrough any ring-forming atom including a ring-forming atom of the fusedaromatic ring. Examples of heterocycloalkyl groups include azetidinyl,azepanyl, dihydrobenzofuranyl, dihydrofuranyl, dihydropyranyl,morpholino, 3-oxa-9-azaspiro[5.5]undecanyl,1-oxa-8-azaspiro[4.5]decanyl, piperidinyl, piperazinyl, oxopiperazinyl,pyranyl, pyrrolidinyl, quinuclidinyl, tetrahydrofuranyl,tetrahydropyranyl, 1,2,3,4-tetrahydroquinolinyl, tropanyl, andthiomorpholino.

At certain places, the definitions or embodiments refer to specificrings (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwiseindicated, these rings can be attached to any ring member provided thatthe valency of the atom is not exceeded. For example, an azetidine ringmay be attached at any position of the ring, whereas an azetidin-3-ylring is attached at the 3-position.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereomers, are intended unless otherwise indicated. Compounds of thepresent invention that contain asymmetrically substituted carbon atomscan be isolated in optically active or racemic forms. Methods on how toprepare optically active forms from optically inactive startingmaterials are known in the art, such as by resolution of racemicmixtures or by stereoselective synthesis. Many geometric isomers ofolefins, C═N double bonds and the like can also be present in thecompounds described herein, and all such stable isomers are contemplatedin the present invention. Cis and trans geometric isomers of thecompounds of the present invention are described and may be isolated asa mixture of isomers or as separated isomeric forms.

Resolution of racemic mixtures of compounds can be carried out by any ofnumerous methods known in the art. One method includes fractionalrecrystallization using a chiral resolving acid which is an opticallyactive, salt-forming organic acid. Suitable resolving agents forfractional recrystallization methods are, e.g., optically active acids,such as the D and L forms of tartaric acid, diacetyltartaric acid,dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or thevarious optically active camphorsulfonic acids such as β-camphorsulfonicacid. Other resolving agents suitable for fractional crystallizationmethods include stereoisomerically pure forms of α-methylbenzylamine(e.g., S and R forms, or diastereomerically pure forms),2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine,cyclohexylethylamine, 1,2-diaminocyclohexane and the like.

Resolution of racemic mixtures can also be carried out by elution on acolumn packed with an optically active resolving agent (e.g.,dinitrobenzoylphenylglycine). Suitable elution solvent composition canbe determined by one skilled in the art.

In some embodiments, the compounds of the invention have the(R)-configuration. In other embodiments, the compounds have the(S)-configuration. In compounds with more than one chiral centers, eachof the chiral centers in the compound may be independently (R) or (S),unless otherwise indicated.

Compounds of the invention also include tautomeric forms. Tautomericforms result from the swapping of a single bond with an adjacent doublebond together with the concomitant migration of a proton. Tautomericforms include prototropic tautomers which are isomeric protonationstates having the same empirical formula and total charge. Exampleprototropic tautomers include ketone enol pairs, amide-imidic acidpairs, lactam lactim pairs, enamine imine pairs, and annular forms wherea proton can occupy two or more positions of a heterocyclic system,e.g., 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and2H-isoindole and 1H- and 2H-pyrazole. Tautomeric forms can be inequilibrium or sterically locked into one form by appropriatesubstitution.

Compounds of the invention can also include all isotopes of atomsoccurring in the intermediates or final compounds. Isotopes includethose atoms having the same atomic number but different mass numbers.For example, isotopes of hydrogen include tritium and deuterium.

The term, “compound,” as used herein is meant to include allstereoisomers, geometric isomers, tautomers and isotopes of thestructures depicted. The term is also meant to refer to compounds of theinventions, regardless of how they are prepared, e.g., synthetically,through biological process (e.g., metabolism or enzyme conversion), or acombination thereof.

All compounds, and pharmaceutically acceptable salts thereof, can befound together with other substances such as water and solvents (e.g.,hydrates and solvates) or can be isolated. When in the solid state, thecompounds described herein and salts thereof may occur in various formsand may, e.g., take the form of solvates, including hydrates. Thecompounds may be in any solid state form, such as a polymorph orsolvate, so unless clearly indicated otherwise, reference in thespecification to compounds and salts thereof should be understood asencompassing any solid state form of the compound.

In some embodiments, the compounds of the invention, or salts thereof,are substantially isolated. By “substantially isolated” is meant thatthe compound is at least partially or substantially separated from theenvironment in which it was formed or detected. Partial separation caninclude, e.g., a composition enriched in the compounds of the invention.Substantial separation can include compositions containing at leastabout 50%, at least about 60%, at least about 70%, at least about 80%,at least about 90%, at least about 95%, at least about 97%, or at leastabout 99% by weight of the compounds of the invention, or salt thereof.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The expressions, “ambient temperature” and “room temperature,” as usedherein, are understood in the art, and refer generally to a temperature,e.g., a reaction temperature, that is about the temperature of the roomin which the reaction is carried out, e.g., a temperature from about 20°C. to about 30° C.

The present invention also includes pharmaceutically acceptable salts ofthe compounds described herein. The term “pharmaceutically acceptablesalts” refers to derivatives of the disclosed compounds wherein theparent compound is modified by converting an existing acid or basemoiety to its salt form. Examples of pharmaceutically acceptable saltsinclude, but are not limited to, mineral or organic acid salts of basicresidues such as amines; alkali or organic salts of acidic residues suchas carboxylic acids; and the like. The pharmaceutically acceptable saltsof the present invention include the non-toxic salts of the parentcompound formed, e.g., from non-toxic inorganic or organic acids. Thepharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, non-aqueousmedia like ether, ethyl acetate, alcohols (e.g., methanol, ethanol,iso-propanol or butanol) or acetonitrile (MeCN) are preferred. Lists ofsuitable salts are found in Remington's Pharmaceutical Sciences, 17^(th)Ed., (Mack Publishing Company, Easton, 1985), p. 1418, Berge et al., J.Pharm. Sci., 1977, 66(1), 1-19 and in Stahl et al., Handbook ofPharmaceutical Salts: Properties, Selection, and Use, (Wiley, 2002). Insome embodiments, the compounds described herein include the N-oxideforms.

II. Synthesis

Compounds of the invention, including salts thereof, can be preparedusing known organic synthesis techniques and can be synthesizedaccording to any of numerous possible synthetic routes, such as those inthe Schemes below.

The reactions for preparing compounds of the invention can be carriedout in suitable solvents which can be readily selected by one of skillin the art of organic synthesis. Suitable solvents can be substantiallynon-reactive with the starting materials (reactants), the intermediatesor products at the temperatures at which the reactions are carried out,e.g., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature. A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected by the skilled artisan.

Preparation of compounds of the invention can involve the protection anddeprotection of various chemical groups. The need for protection anddeprotection, and the selection of appropriate protecting groups, can bereadily determined by one skilled in the art. The chemistry ofprotecting groups is described, e.g., in Kocienski, Protecting Groups,(Thieme, 2007); Robertson, Protecting Group Chemistry, (OxfordUniversity Press, 2000); Smith et al., March's Advanced OrganicChemistry: Reactions, Mechanisms, and Structure, 6^(th) Ed. (Wiley,2007); Peturssion et al., “Protecting Groups in Carbohydrate Chemistry,”J. Chem. Educ., 1997, 74(11), 1297; and Wuts et al., Protective Groupsin Organic Synthesis, 4th Ed., (Wiley, 2006).

Reactions can be monitored according to any suitable method known in theart. For example, product formation can be monitored by spectroscopicmeans, such as nuclear magnetic resonance spectroscopy (e.g., ¹H or¹³C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), massspectrometry or by chromatographic methods such as high performanceliquid chromatography (HPLC) or thin layer chromatography (TLC).

The Schemes below provide general guidance in connection with preparingthe compounds of the invention. One skilled in the art would understandthat the preparations shown in the Schemes can be modified or optimizedusing general knowledge of organic chemistry to prepare variouscompounds of the invention.

Compounds of Formula (I) can be prepared, e.g., using a process asillustrated in Schemes 1-7.

Compounds of formula 1-7 can be synthesized as shown in Scheme 1. Aselective coupling of the iodide 1-1 with compounds of formula 1-2 [M isB(OR)₂, Sn(Alkyl)₃, or Zn-Hal] under suitable Suzuki couplingconditions, Stille coupling conditions, or Negishi coupling conditionscan give derivatives of formula 1-3. The resulting chloride 1-3 can beconverted to its boronic esters or stannanes of formula 1-4 in thepresence of a suitable palladium catalyst. Another palladium catalyzedcoupling of the resulting compounds of formula 1-4 with a commerciallyavailable bromide or iodide building block 1-5 (e.g. Hal is Br or I)under suitable Suzuki or Stille coupling conditions can give compoundsof formula 1-6. After removal of Boc on the piperidine under acidiccondition (trifluoroacetic acid or hydrochloric acid), the substitutionof R¹⁴ can be introduced to the resulting secondary amine by a reductiveamination with the corresponding aldehydes or ketones or an alkylationwith the corresponding alkyl halides to provide the desired compounds offormula 1-7.

Similarly, compounds of formula 2-4, with C—N bonding between the five-and six-membered aromatic rings, can be synthesized as shown in Scheme2. Compounds of formula 2-1 (e.g., Hal is Cl or Br) can be preparedusing similar conditions as described in Scheme 1. The C—N bond can beformed under suitable Buchwald-Hartwig amination conditions with acommercial amine moiety of formula 2-2 to give compounds of formula 2-3.After removal of Boc on the piperidine under acidic condition, thesubstitution of R¹⁴ can be introduced to the resulting secondary amineby a reductive amination with the corresponding aldehydes or ketones toprovide the desired compounds of formula 2-4.

Alternatively, compounds of formula 3-7 can be synthesized as shown inScheme 3. Selective conversion of the L group in compound 3-1 (L is Br,I or OTf) to boronic ester can be achieved in the presence of a suitablepalladium catalyst and bis(pinacolato)diboron to give boronic ester offormula 3-2. Selective Suzuki coupling of heteroaryl bromide 3-3 withboronic ester 3-2 can give biaryl chloride 3-4. Installation of Cy ringcan be achieved using similar conditions as described in Scheme 1 bycoupling biaryl chloride 3-4 with compound 3-5 to give compounds offormula 3-6. Removal of Boc protecting group followed by reductiveamination with the corresponding aldehydes or ketones can provide thedesired compounds of formula 3-7.

Thioazole compounds of formula 4-7, with substitutions on the piperidinering, can be synthesized as shown in Scheme 4. The Boc protectedoxo-piperidine of formula 4-1 can be brominated at the ketone α positioneither by treatment with bromine, or by a sequence of TMS enol etherformation and NBS bromination. The resulting bromide 4-2 can beconverted to the aminothiazole 4-3 via reacting with thiourea inalcoholic solvents at elevated temperature. The amine group in 4-3 canbe converted to halide under Sandermeyer conditions (e.g., in thepresence of ^(t)BuONO and CuBr₂) to give bromothiazole 4-4. Compound offormula 4-5 [M′ is B(OR)₂ or SnBu₃] can be prepared using similarconditions as described in Scheme 1. Coupling of bromothiazole 4-4 withcompound 4-5 can be achieved under suitable Suzuki coupling conditionsor Stille coupling conditions to give compounds of formula 4-6. Afterremoval of Boc on the coupling product 4-6 under acidic condition(trifluoroacetic acid or hydrochloric acid), the substitution of R¹⁴ canbe introduced to the resulting secondary amine by a reductive aminationwith the corresponding aldehydes or ketones to provide the desiredcompounds of formula 4-7.

Alternatively, oxazole derivatives of formula 5-7 can be synthesizedaccording to the synthetic route as outlined in Scheme 5. Condensationof carboxylic acid 5-1 with amino, hydroxyl-disubstituted pyridine 5-2in the presence of a condensation reagent (such as cyanuric chloride)can produce compounds of formula 5-3. Alkylation of the pyridine in 5-3with benzyl bromide can give the quaternary salt 5-4 and subsequentreduction of 5-4 with NaBH₄ can lead to compound 5-5. Removal of thebenzyl group using Pd/C under hydrogenation conditions can give compound5-6. The R¹⁴ group can be introduced under standard alkylationconditions or reductive amination conditions to give the final product5-7.

Compounds of formula 6-5 can also be synthesized using conditions asshown in Scheme 6. Cyclization of α-bromo ketone derivatives of formula6-1 with amino pyrazine 6-2 can give the heteroaryl compounds 6-3.Selective reduction of the pyrazine ring in compound 6-3 can be achievedby treating with LiBH₄ or using a similar reaction sequence as describedin Scheme 5 to give compound 6-4. Similarly, the R¹⁴ group can beintroduced under alkylation conditions or reductive amination conditionsto give the desired product 6-5.

Alternatively, compounds of formula 7-5 can be synthesized as shown inScheme 7. Coupling of compound 7-1 [M′ is B(OR)₂ or SnBu₃] withheteroaryl halide 7-2 (Hal is Cl, Br or I) can be achieved undersuitable Suzuki coupling conditions or Stille coupling conditions togive compounds of formula 7-3. Selective reduction of the heteroarylring in 7-3 using similar conditions as described in Scheme 5 or Scheme6 can give compound 7-4. Installation of R¹⁴ group can be achievedsimilarly under alkylation conditions or reductive amination conditionsto give compound 7-5.

III. Uses of the Compounds

Compounds of the present disclosure can inhibit the activity ofPD-1/PD-L1 protein/protein interaction and, thus, are useful in treatingdiseases and disorders associated with activity of PD-1 and the diseasesand disorders associated with PD-L1 including its interaction with otherproteins such as PD-1 and B7-1 (CD80). In certain embodiments, thecompounds of the present disclosure, or pharmaceutically acceptablesalts or stereoisomers thereof, are useful for therapeuticadministration to enhance, stimulate and/or increase immunity in canceror chronic infection, including enhancement of response to vaccination.In some embodiments, the present disclosure provides a method forinhibiting or blocking the PD-1/PD-L1 protein/protein interaction. Themethod includes administering to an individual or a patient a compoundof Formula (I) or any of the formulas as described herein or of acompound as recited in any of the claims and described herein, or apharmaceutically acceptable salt or a stereoisomer thereof. Thecompounds of the present disclosure can be used alone, in combinationwith other agents or therapies or as an adjuvant or neoadjuvant for thetreatment of diseases or disorders, including cancer or infectiondiseases. For the uses described herein, any of the compounds of thedisclosure, including any of the embodiments thereof, may be used.

The compounds of the present disclosure inhibit the PD-1/PD-L1protein/protein interaction, resulting in a PD-1 pathway blockade. Theblockade of PD-1 can enhance the immune response to cancerous cells andinfectious diseases in mammals, including humans. In some embodiments,the present disclosure provides treatment of an individual or a patientin vivo using a compound of Formula (I) or a salt or stereoisomerthereof such that growth of cancerous tumors is inhibited. A compound ofFormula (I) or of any of the formulas as described herein, or a compoundas recited in any of the claims and described herein, or a salt orstereoisomer thereof, can be used to inhibit the growth of canceroustumors. Alternatively, a compound of Formula (I) or of any of theformulas as described herein, or a compound as recited in any of theclaims and described herein, or a salt or stereoisomer thereof, can beused in conjunction with other agents or standard cancer treatments, asdescribed below. In one embodiment, the present disclosure provides amethod for inhibiting growth of tumor cells in vitro. The methodincludes contacting the tumor cells in vitro with a compound of Formula(I) or of any of the formulas as described herein, or of a compound asrecited in any of the claims and described herein, or of a salt orstereoisomer thereof. In another embodiment, the present disclosureprovides a method for inhibiting growth of tumor cells in an individualor a patient. The method includes administering to the individual orpatient in need thereof a therapeutically effective amount of a compoundof Formula (I) or of any of the formulas as described herein, or of acompound as recited in any of the claims and described herein, or a saltor a stereoisomer thereof.

In some embodiments, provided herein is a method for treating cancer.The method includes administering to a patient in need thereof, atherapeutically effective amount of a compound of Formula (I) or any ofthe formulas as described herein, a compound as recited in any of theclaims and described herein, or a salt thereof. Examples of cancersinclude those whose growth may be inhibited using compounds of thedisclosure and cancers typically responsive to immunotherapy.

In some embodiments, the present disclosure provides a method ofenhancing, stimulating and/or increasing the immune response in apatient. The method includes administering to the patient in needthereof a therapeutically effective amount of a compound of Formula (I)or any of the formulas as described herein, a compound as recited in anyof the claims and described herein, or a salt thereof.

Examples of cancers that are treatable using the compounds of thepresent disclosure include, but are not limited to, bone cancer,pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous orintraocular malignant melanoma, uterine cancer, ovarian cancer, rectalcancer, cancer of the anal region, stomach cancer, testicular cancer,uterine cancer, carcinoma of the fallopian tubes, carcinoma of theendometrium, endometrial cancer, carcinoma of the cervix, carcinoma ofthe vagina, carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin'slymphoma, cancer of the esophagus, cancer of the small intestine, cancerof the endocrine system, cancer of the thyroid gland, cancer of theparathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue,cancer of the urethra, cancer of the penis, chronic or acute leukemiasincluding acute myeloid leukemia, chronic myeloid leukemia, acutelymphoblastic leukemia, chronic lymphocytic leukemia, solid tumors ofchildhood, lymphocytic lymphoma, cancer of the bladder, cancer of thekidney or urethra, carcinoma of the renal pelvis, neoplasm of thecentral nervous system (CNS), primary CNS lymphoma, tumor angiogenesis,spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi'ssarcoma, epidermoid cancer, squamous cell cancer, T-cell lymphoma,environmentally induced cancers including those induced by asbestos, andcombinations of said cancers. The compounds of the present disclosureare also useful for the treatment of metastatic cancers, especiallymetastatic cancers that express PD-L1.

In some embodiments, cancers treatable with compounds of the presentdisclosure include melanoma (e.g., metastatic malignant melanoma), renalcancer (e.g. clear cell carcinoma), prostate cancer (e.g. hormonerefractory prostate adenocarcinoma), breast cancer, colon cancer andlung cancer (e.g. non-small cell lung cancer). Additionally, thedisclosure includes refractory or recurrent malignancies whose growthmay be inhibited using the compounds of the disclosure.

In some embodiments, cancers that are treatable using the compounds ofthe present disclosure include, but are not limited to, solid tumors(e.g., prostate cancer, colon cancer, esophageal cancer, endometrialcancer, ovarian cancer, uterine cancer, renal cancer, hepatic cancer,pancreatic cancer, gastric cancer, breast cancer, lung cancer, cancersof the head and neck, thyroid cancer, glioblastoma, sarcoma, bladdercancer, etc.), hematological cancers (e.g., lymphoma, leukemia such asacute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML),chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML),DLBCL, mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsed orrefractory NHL and recurrent follicular), Hodgkin lymphoma or multiplemyeloma) and combinations of said cancers.

PD-1 pathway blockade with compounds of the present disclosure can alsobe used for treating infections such as viral, bacteria. fungus andparasite infections. The present disclosure provides a method fortreating infections such as viral infections. The method includesadministering to a patient in need thereof, a therapeutically effectiveamount of a compound of Formula (I) or any of the formulas as describedherein, a compound as recited in any of the claims and described herein,a salt thereof. Examples of viruses causing infections treatable bymethods of the present disclosure include, but are not limit to, humanimmunodeficiency virus, human papillomavirus, influenza, hepatitis A, B,C or D viruses, adenovirus, poxvirus, herpes simplex viruses, humancytomegalovirus, severe acute respiratory syndrome virus, ebola virus,and measles virus. In some embodiments, viruses causing infectionstreatable by methods of the present disclosure include, but are notlimit to, hepatitis (A, B, or C), herpes virus (e.g., VZV, HSV-1, HAV-6,HSV-II, and CMV, Epstein Barr virus), adenovirus, influenza virus,flaviviruses, echovirus, rhinovirus, coxsackie virus, cornovirus,respiratory syncytial virus, mumpsvirus, rotavirus, measles virus,rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus,papillomavirus, molluscum virus, poliovirus, rabies virus, JC virus andarboviral encephalitis virus.

The present disclosure provides a method for treating bacterialinfections. The method includes administering to a patient in needthereof, a therapeutically effective amount of a compound of Formula (I)or any of the formulas as described herein, a compound as recited in anyof the claims and described herein, or a salt thereof. Non-limitingexamples of pathogenic bacteria causing infections treatable by methodsof the disclosure include chlamydia, rickettsial bacteria, mycobacteria,staphylococci, streptococci, pneumonococci, meningococci and conococci,klebsiella, proteus, serratia, pseudomonas, legionella, diphtheria,salmonella, bacilli, cholera, tetanus, botulism, anthrax, plague,leptospirosis, and Lyme's disease bacteria.

The present disclosure provides a method for treating fungus infections.The method includes administering to a patient in need thereof, atherapeutically effective amount of a compound of Formula (I) or any ofthe formulas as described herein, a compound as recited in any of theclaims and described herein, or a salt thereof. Non-limiting examples ofpathogenic fungi causing infections treatable by methods of thedisclosure include Candida (albicans, krusei, glabrata, tropicalis,etc.), Cryptococcus neoformans, Aspergillus (fumigatus, niger, etc.),Genus Mucorales (mucor, absidia, rhizophus), Sporothrix schenkii,Blastomyces dermatitidis, Paracoccidioides brasiliensis, Coccidioidesimmitis and Histoplasma capsulatum.

The present disclosure provides a method for treating parasiteinfections. The method includes administering to a patient in needthereof, a therapeutically effective amount of a compound of Formula (I)or any of the formulas as described herein, a compound as recited in anyof the claims and described herein, or a salt thereof. Non-limitingexamples of pathogenic parasites causing infections treatable by methodsof the disclosure include Entamoeba histolytica, Balantidium coli,Naegleria fowleri, Acanthamoeba sp., Giardia lambia, Cryptosporidiumsp., Pneumocystis carinii, Plasmodium vivax, Babesia microti,Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasmagondi, and Nippostrongylus brasiliensis.

The terms “individual” or “patient,” used interchangeably, refer to anyanimal, including mammals, preferably mice, rats, other rodents,rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and mostpreferably humans.

The phrase “therapeutically effective amount” refers to the amount ofactive compound or pharmaceutical agent that elicits the biological ormedicinal response in a tissue, system, animal, individual or human thatis being sought by a researcher, veterinarian, medical doctor or otherclinician.

As used herein, the term “treating” or “treatment” refers to one or moreof (1) inhibiting the disease; e.g., inhibiting a disease, condition ordisorder in an individual who is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,arresting further development of the pathology and/or symptomatology);and (2) ameliorating the disease; e.g., ameliorating a disease,condition or disorder in an individual who is experiencing or displayingthe pathology or symptomatology of the disease, condition or disorder(i.e., reversing the pathology and/or symptomatology) such as decreasingthe severity of disease.

In some embodiments, the compounds of the invention are useful inpreventing or reducing the risk of developing any of the diseasesreferred to herein; e.g., preventing or reducing the risk of developinga disease, condition or disorder in an individual who may be predisposedto the disease, condition or disorder but does not yet experience ordisplay the pathology or symptomatology of the disease.

Combination Therapies

Cancer cell growth and survival can be impacted by multiple signalingpathways. Thus, it is useful to combine differentenzyme/protein/receptor inhibitors, exhibiting different preferences inthe targets which they modulate the activities of, to treat suchconditions. Targeting more than one signaling pathway (or more than onebiological molecule involved in a given signaling pathway) may reducethe likelihood of drug-resistance arising in a cell population, and/orreduce the toxicity of treatment.

The compounds of the present disclosure can be used in combination withone or more other enzyme/protein/receptor inhibitors for the treatmentof diseases, such as cancer or infections. Examples of cancers includesolid tumors and liquid tumors, such as blood cancers. Examples ofinfections include viral infections, bacterial infections, fungusinfections or parasite infections. For example, the compounds of thepresent disclosure can be combined with one or more inhibitors of thefollowing kinases for the treatment of cancer: Akt1, Akt2, Akt3, TGF-PR,PKA, PKG, PKC, CaM-kinase, phosphorylase kinase, MEKK, ERK, MAPK, mTOR,EGFR, HER2, HER3, HER4, INS-R, IGF-1R, IR-R, PDGFαR, PDGFβR, CSFIR, KIT,FLK-II, KDR/FLK-1, FLK-4, flt-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, Ron,Sea, TRKA, TRKB, TRKC, FLT3, VEGFR/Flt2, Flt4, EphA1, EphA2, EphA3,EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK, ABL,ALK and B-Raf. In some embodiments, the compounds of the presentdisclosure can be combined with one or more of the following inhibitorsfor the treatment of cancer or infections. Non-limiting examples ofinhibitors that can be combined with the compounds of the presentdisclosure for treatment of cancer and infections include an FGFRinhibitor (FGFR1, FGFR2, FGFR3 or FGFR4, e.g., INCB54828, INCB62079 andINCB63904), a JAK inhibitor (JAK1 and/or JAK2, e.g., ruxolitinib,baricitinib or INCB39110), an IDO inhibitor (e.g., epacadostat andNLG919), an LSD1 inhibitor (e.g., INCB59872 and INCB60003), a TDOinhibitor, a PI3K-delta inhibitor, a PI3K-gamma inhibitor such asPI3K-gamma selective inhibitor (e.g., INCB50797), a Pim inhibitor, aCSF1R inhibitor, a TAM receptor tyrosine kinases (Tyro-3, Axl, and Mer),an angiogenesis inhibitor, an interleukin receptor inhibitor, bromo andextra terminal family members inhibitors (for example, bromodomaininhibitors or BET inhibitors such as INCB54329 and INCB57643) and anadenosine receptor antagonist or combinations thereof.

Compounds of the present disclosure can be used in combination with oneor more immune checkpoint inhibitors. Exemplary immune checkpointinhibitors include inhibitors against immune checkpoint molecules suchas CD27, CD28, CD40, CD122, CD96, CD73, CD47, OX40, GITR, CSF1R, JAK,PI3K delta, PI3K gamma, TAM, arginase, CD137 (also known as 4-1BB),ICOS, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, PD-1, PD-L1and PD-L2. In some embodiments, the immune checkpoint molecule is astimulatory checkpoint molecule selected from CD27, CD28, CD40, ICOS,OX40, GITR and CD137. In some embodiments, the immune checkpointmolecule is an inhibitory checkpoint molecule selected from A2AR, B7-H3,B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, TIM3, and VISTA. In someembodiments, the compounds provided herein can be used in combinationwith one or more agents selected from KIR inhibitors, TIGIT inhibitors,LAIR1 inhibitors, CD160 inhibitors, 2B4 inhibitors and TGFR betainhibitors.

In some embodiments, the inhibitor of an immune checkpoint molecule isanti-PD1 antibody, anti-PD-L1 antibody, or anti-CTLA-4 antibody.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-1, e.g., an anti-PD-1 monoclonal antibody. In someembodiments, the anti-PD-1 monoclonal antibody is nivolumab,pembrolizumab (also known as MK-3475), pidilizumab, SHR-1210, PDR001, orAMP-224. In some embodiments, the anti-PD-1 monoclonal antibody isnivolumab or pembrolizumab. In some embodiments, the anti-PD1 antibodyis pembrolizumab. In some embodiments, the anti PD-1 antibody isSHR-1210.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of PD-L1, e.g., an anti-PD-L1 monoclonal antibody. In someembodiments, the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736,MPDL3280A (also known as RG7446), or MSB0010718C. In some embodiments,the anti-PD-L1 monoclonal antibody is MPDL3280A or MEDI4736.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody. In someembodiments, the anti-CTLA-4 antibody is ipilimumab.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of LAG3, e.g., an anti-LAG3 antibody. In some embodiments,the anti-LAG3 antibody is BMS-986016 or LAG525.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of GITR, e.g., an anti-GITR antibody. In some embodiments,the anti-GITR antibody is TRX518 or MK-4166.

In some embodiments, the inhibitor of an immune checkpoint molecule isan inhibitor of OX40, e.g., an anti-OX40 antibody or OX40L fusionprotein. In some embodiments, the anti-OX40 antibody is MEDI0562. Insome embodiments, the OX40L fusion protein is MEDI6383.

Compounds of the present disclosure can be used in combination with oneor more agents for the treatment of diseases such as cancer. In someembodiments, the agent is an alkylating agent, a proteasome inhibitor, acorticosteroid, or an immunomodulatory agent. Examples of an alkylatingagent include cyclophosphamide (CY), melphalan (MEL), and bendamustine.In some embodiments, the proteasome inhibitor is carfilzomib. In someembodiments, the corticosteroid is dexamethasone (DEX). In someembodiments, the immunomodulatory agent is lenalidomide (LEN) orpomalidomide (POM).

The compounds of the present disclosure can further be used incombination with other methods of treating cancers, for example bychemotherapy, irradiation therapy, tumor-targeted therapy, adjuvanttherapy, immunotherapy or surgery. Examples of immunotherapy includecytokine treatment (e.g., interferons, GM-CSF, G-CSF, IL-2), CRS-207immunotherapy, cancer vaccine, monoclonal antibody, adoptive T celltransfer, oncolytic virotherapy and immunomodulating small molecules,including thalidomide or JAK1/2 inhibitor and the like. The compoundscan be administered in combination with one or more anti-cancer drugs,such as a chemotherapeutics. Example chemotherapeutics include any of:abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol,altretamine, anastrozole, arsenic trioxide, asparaginase, azacitidine,bevacizumab, bexarotene, baricitinib, bleomycin, bortezombi, bortezomib,busulfan intravenous, busulfan oral, calusterone, capecitabine,carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine,clofarabine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin,dalteparin sodium, dasatinib, daunorubicin, decitabine, denileukin,denileukin diftitox, dexrazoxane, docetaxel, doxorubicin, dromostanolonepropionate, eculizumab, epirubicin, erlotinib, estramustine, etoposidephosphate, etoposide, exemestane, fentanyl citrate, filgrastim,floxuridine, fludarabine, fluorouracil, fulvestrant, gefitinib,gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelinacetate, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinibmesylate, interferon alfa 2a, irinotecan, lapatinib ditosylate,lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole,lomustine, meclorethamine, megestrol acetate, melphalan, mercaptopurine,methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone,nandrolone phenpropionate, nelarabine, nofetumomab, oxaliplatin,paclitaxel, pamidronate, panitumumab, pegaspargase, pegfilgrastim,pemetrexed disodium, pentostatin, pipobroman, plicamycin, procarbazine,quinacrine, rasburicase, rituximab, ruxolitinib, sorafenib,streptozocin, sunitinib, sunitinib maleate, tamoxifen, temozolomide,teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan,toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard,valrubicin, vinblastine, vincristine, vinorelbine, vorinostat andzoledronate.

Other anti-cancer agent(s) include antibody therapeutics such astrastuzumab (Herceptin), antibodies to costimulatory molecules such asCTLA-4 (e.g., ipilimumab), 4-1BB, antibodies to PD-1 and PD-L1, orantibodies to cytokines (IL-10, TGF-β, etc.). Examples of antibodies toPD-1 and/or PD-L1 that can be combined with compounds of the presentdisclosure for the treatment of cancer or infections such as viral,bacteria, fungus and parasite infections include, but are not limitedto, nivolumab, pembrolizumab, MPDL3280A, MEDI-4736 and SHR-1210.

The compounds of the present disclosure can further be used incombination with one or more anti-inflammatory agents, steroids,immunosuppressants or therapeutic antibodies.

The compounds of Formula (I) or any of the formulas as described herein,a compound as recited in any of the claims and described herein, orsalts thereof can be combined with another immunogenic agent, such ascancerous cells, purified tumor antigens (including recombinantproteins, peptides, and carbohydrate molecules), cells, and cellstransfected with genes encoding immune stimulating cytokines.Non-limiting examples of tumor vaccines that can be used includepeptides of melanoma antigens, such as peptides of gp100, MAGE antigens,Trp-2, MARTI and/or tyrosinase, or tumor cells transfected to expressthe cytokine GM-CSF.

The compounds of Formula (I) or any of the formulas as described herein,a compound as recited in any of the claims and described herein, orsalts thereof can be used in combination with a vaccination protocol forthe treatment of cancer. In some embodiments, the tumor cells aretransduced to express GM-CSF. In some embodiments, tumor vaccinesinclude the proteins from viruses implicated in human cancers such asHuman Papilloma Viruses (HPV), Hepatitis Viruses (HBV and HCV) andKaposi's Herpes Sarcoma Virus (KHSV). In some embodiments, the compoundsof the present disclosure can be used in combination with tumor specificantigen such as heat shock proteins isolated from tumor tissue itself.In some embodiments, the compounds of Formula (I) or any of the formulasas described herein, a compound as recited in any of the claims anddescribed herein, or salts thereof can be combined with dendritic cellsimmunization to activate potent anti-tumor responses.

The compounds of the present disclosure can be used in combination withbispecific macrocyclic peptides that target Fe alpha or Fe gammareceptor-expressing effectors cells to tumor cells. The compounds of thepresent disclosure can also be combined with macrocyclic peptides thatactivate host immune responsiveness.

The compounds of the present disclosure can be used in combination withbone marrow transplant for the treatment of a variety of tumors ofhematopoietic origin.

The compounds of Formula (I) or any of the formulas as described herein,a compound as recited in any of the claims and described herein, orsalts thereof can be used in combination with vaccines, to stimulate theimmune response to pathogens, toxins, and self antigens. Examples ofpathogens for which this therapeutic approach may be particularlyuseful, include pathogens for which there is currently no effectivevaccine, or pathogens for which conventional vaccines are less thancompletely effective. These include, but are not limited to, HIV,Hepatitis (A, B, & C), Influenza, Herpes, Giardia, Malaria, Leishmania,Staphylococcus aureus, Pseudomonas Aeruginosa.

Viruses causing infections treatable by methods of the presentdisclosure include, but are not limit to human papillomavirus,influenza, hepatitis A, B, C or D viruses, adenovirus, poxvirus, herpessimplex viruses, human cytomegalovirus, severe acute respiratorysyndrome virus, ebola virus, measles virus, herpes virus (e.g., VZV,HSV-1, HAV-6, HSV-II, and CMV, Epstein Barr virus), flaviviruses,echovirus, rhinovirus, coxsackie virus, cornovirus, respiratorysyncytial virus, mumpsvirus, rotavirus, measles virus, rubella virus,parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus,molluscum virus, poliovirus, rabies virus, JC virus and arboviralencephalitis virus.

Pathogenic bacteria causing infections treatable by methods of thedisclosure include, but are not limited to, chlamydia, rickettsialbacteria, mycobacteria, staphylococci, streptococci, pneumonococci,meningococci and conococci, klebsiella, proteus, serratia, pseudomonas,legionella, diphtheria, salmonella, bacilli, cholera, tetanus, botulism,anthrax, plague, leptospirosis, and Lyme's disease bacteria.

Pathogenic fungi causing infections treatable by methods of thedisclosure include, but are not limited to, Candida (albicans, krusei,glabrata, tropicalis, etc.), Cryptococcus neoformans, Aspergillus(fumigatus, niger, etc.), Genus Mucorales (mucor, absidia, rhizophus),Sporothrix schenkii, Blastomyces dermatitidis, Paracoccidioidesbrasiliensis, Coccidioides immitis and Histoplasma capsulatum.

Pathogenic parasites causing infections treatable by methods of thedisclosure include, but are not limited to, Entamoeba histolytica,Balantidium coli, Naegleria fowleri, Acanthamoeba sp., Giardia lambia,Cryptosporidium sp., Pneumocystis carinii, Plasmodium vivax, Babesiamicroti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani,Toxoplasma gondi, and Nippostrongylus brasiliensis.

When more than one pharmaceutical agent is administered to a patient,they can be administered simultaneously, separately, sequentially, or incombination (e.g., for more than two agents).

IV. Formulation, Dosage Forms and Administration

When employed as pharmaceuticals, the compounds of the presentdisclosure can be administered in the form of pharmaceuticalcompositions. Thus the present disclosure provides a compositioncomprising a compound of Formula (I) or any of the formulas as describedherein, a compound as recited in any of the claims and described herein,or a pharmaceutically acceptable salt thereof, or any of the embodimentsthereof, and at least one pharmaceutically acceptable carrier orexcipient. These compositions can be prepared in a manner well known inthe pharmaceutical art, and can be administered by a variety of routes,depending upon whether local or systemic treatment is indicated and uponthe area to be treated. Administration may be topical (includingtransdermal, epidermal, ophthalmic and to mucous membranes includingintranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalationor insufflation of powders or aerosols, including by nebulizer;intratracheal or intranasal), oral or parenteral. Parenteraladministration includes intravenous, intraarterial, subcutaneous,intraperitoneal intramuscular or injection or infusion; or intracranial,e.g., intrathecal or intraventricular, administration. Parenteraladministration can be in the form of a single bolus dose, or may be,e.g., by a continuous perfusion pump. Pharmaceutical compositions andformulations for topical administration may include transdermal patches,ointments, lotions, creams, gels, drops, suppositories, sprays, liquidsand powders. Conventional pharmaceutical carriers, aqueous, powder oroily bases, thickeners and the like may be necessary or desirable.

This invention also includes pharmaceutical compositions which contain,as the active ingredient, the compound of the present disclosure or apharmaceutically acceptable salt thereof, in combination with one ormore pharmaceutically acceptable carriers or excipients. In someembodiments, the composition is suitable for topical administration. Inmaking the compositions of the invention, the active ingredient istypically mixed with an excipient, diluted by an excipient or enclosedwithin such a carrier in the form of, e.g., a capsule, sachet, paper, orother container. When the excipient serves as a diluent, it can be asolid, semi-solid, or liquid material, which acts as a vehicle, carrieror medium for the active ingredient. Thus, the compositions can be inthe form of tablets, pills, powders, lozenges, sachets, cachets,elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solidor in a liquid medium), ointments containing, e.g., up to 10% by weightof the active compound, soft and hard gelatin capsules, suppositories,sterile injectable solutions and sterile packaged powders.

In preparing a formulation, the active compound can be milled to providethe appropriate particle size prior to combining with the otheringredients. If the active compound is substantially insoluble, it canbe milled to a particle size of less than 200 mesh. If the activecompound is substantially water soluble, the particle size can beadjusted by milling to provide a substantially uniform distribution inthe formulation, e.g., about 40 mesh.

The compounds of the invention may be milled using known millingprocedures such as wet milling to obtain a particle size appropriate fortablet formation and for other formulation types. Finely divided(nanoparticulate) preparations of the compounds of the invention can beprepared by processes known in the art see, e.g., WO 2002/000196.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

In some embodiments, the pharmaceutical composition comprises silicifiedmicrocrystalline cellulose (SMCC) and at least one compound describedherein, or a pharmaceutically acceptable salt thereof. In someembodiments, the silicified microcrystalline cellulose comprises about98% microcrystalline cellulose and about 2% silicon dioxide w/w.

In some embodiments, the composition is a sustained release compositioncomprising at least one compound described herein, or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptablecarrier or excipient. In some embodiments, the composition comprises atleast one compound described herein, or a pharmaceutically acceptablesalt thereof, and at least one component selected from microcrystallinecellulose, lactose monohydrate, hydroxypropyl methylcellulose andpolyethylene oxide. In some embodiments, the composition comprises atleast one compound described herein, or a pharmaceutically acceptablesalt thereof, and microcrystalline cellulose, lactose monohydrate andhydroxypropyl methylcellulose. In some embodiments, the compositioncomprises at least one compound described herein, or a pharmaceuticallyacceptable salt thereof, and microcrystalline cellulose, lactosemonohydrate and polyethylene oxide. In some embodiments, the compositionfurther comprises magnesium stearate or silicon dioxide. In someembodiments, the microcrystalline cellulose is Avicel PH102™. In someembodiments, the lactose monohydrate is Fast-flo 316™. In someembodiments, the hydroxypropyl methylcellulose is hydroxypropylmethylcellulose 2208 K4M (e.g., Methocel K4 M Premier™) and/orhydroxypropyl methylcellulose 2208 K100LV (e.g., Methocel K00LV™) Insome embodiments, the polyethylene oxide is polyethylene oxide WSR 1105(e.g., Polyox WSR 1105™).

In some embodiments, a wet granulation process is used to produce thecomposition. In some embodiments, a dry granulation process is used toproduce the composition.

The compositions can be formulated in a unit dosage form, each dosagecontaining from about 5 to about 1,000 mg (1 g), more usually about 100mg to about 500 mg, of the active ingredient. In some embodiments, eachdosage contains about 10 mg of the active ingredient. In someembodiments, each dosage contains about 50 mg of the active ingredient.In some embodiments, each dosage contains about 25 mg of the activeingredient. The term “unit dosage forms” refers to physically discreteunits suitable as unitary dosages for human subjects and other mammals,each unit containing a predetermined quantity of active materialcalculated to produce the desired therapeutic effect, in associationwith a suitable pharmaceutical excipient.

The components used to formulate the pharmaceutical compositions are ofhigh purity and are substantially free of potentially harmfulcontaminants (e.g., at least National Food grade, generally at leastanalytical grade, and more typically at least pharmaceutical grade).Particularly for human consumption, the composition is preferablymanufactured or formulated under Good Manufacturing Practice standardsas defined in the applicable regulations of the U.S. Food and DrugAdministration. For example, suitable formulations may be sterile and/orsubstantially isotonic and/or in full compliance with all GoodManufacturing Practice regulations of the U.S. Food and DrugAdministration.

The active compound may be effective over a wide dosage range and isgenerally administered in a therapeutically effective amount. It will beunderstood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms and the like.

The therapeutic dosage of a compound of the present invention can varyaccording to, e.g., the particular use for which the treatment is made,the manner of administration of the compound, the health and conditionof the patient, and the judgment of the prescribing physician. Theproportion or concentration of a compound of the invention in apharmaceutical composition can vary depending upon a number of factorsincluding dosage, chemical characteristics (e.g., hydrophobicity), andthe route of administration. For example, the compounds of the inventioncan be provided in an aqueous physiological buffer solution containingabout 0.1 to about 10% w/v of the compound for parenteraladministration. Some typical dose ranges are from about 1 μg/kg to about1 g/kg of body weight per day. In some embodiments, the dose range isfrom about 0.01 mg/kg to about 100 mg/kg of body weight per day. Thedosage is likely to depend on such variables as the type and extent ofprogression of the disease or disorder, the overall health status of theparticular patient, the relative biological efficacy of the compoundselected, formulation of the excipient, and its route of administration.Effective doses can be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, the active ingredient istypically dispersed evenly throughout the composition so that thecomposition can be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulation isthen subdivided into unit dosage forms of the type described abovecontaining from, e.g., about 0.1 to about 1000 mg of the activeingredient of the present invention.

The tablets or pills of the present invention can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permit theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol and cellulose acetate.

The liquid forms in which the compounds and compositions of the presentinvention can be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions can be nebulized by use of inert gases. Nebulized solutionsmay be breathed directly from the nebulizing device or the nebulizingdevice can be attached to a face mask, tent, or intermittent positivepressure breathing machine. Solution, suspension, or powder compositionscan be administered orally or nasally from devices which deliver theformulation in an appropriate manner.

Topical formulations can contain one or more conventional carriers. Insome embodiments, ointments can contain water and one or morehydrophobic carriers selected from, e.g., liquid paraffin,polyoxyethylene alkyl ether, propylene glycol, white Vaseline, and thelike. Carrier compositions of creams can be based on water incombination with glycerol and one or more other components, e.g.,glycerinemonostearate, PEG-glycerinemonostearate and cetylstearylalcohol. Gels can be formulated using isopropyl alcohol and water,suitably in combination with other components such as, e.g., glycerol,hydroxyethyl cellulose, and the like. In some embodiments, topicalformulations contain at least about 0.1, at least about 0.25, at leastabout 0.5, at least about 1, at least about 2 or at least about 5 wt %of the compound of the invention. The topical formulations can besuitably packaged in tubes of, e.g., 100 g which are optionallyassociated with instructions for the treatment of the select indication,e.g., psoriasis or other skin condition.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.Effective doses will depend on the disease condition being treated aswell as by the judgment of the attending clinician depending uponfactors such as the severity of the disease, the age, weight and generalcondition of the patient and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers or stabilizers will resultin the formation of pharmaceutical salts.

The therapeutic dosage of a compound of the present invention can varyaccording to, e.g., the particular use for which the treatment is made,the manner of administration of the compound, the health and conditionof the patient, and the judgment of the prescribing physician. Theproportion or concentration of a compound of the invention in apharmaceutical composition can vary depending upon a number of factorsincluding dosage, chemical characteristics (e.g., hydrophobicity), andthe route of administration. For example, the compounds of the inventioncan be provided in an aqueous physiological buffer solution containingabout 0.1 to about 10% w/v of the compound for parenteraladministration. Some typical dose ranges are from about 1 μg/kg to about1 g/kg of body weight per day. In some embodiments, the dose range isfrom about 0.01 mg/kg to about 100 mg/kg of body weight per day. Thedosage is likely to depend on such variables as the type and extent ofprogression of the disease or disorder, the overall health status of theparticular patient, the relative biological efficacy of the compoundselected, formulation of the excipient, and its route of administration.Effective doses can be extrapolated from dose-response curves derivedfrom in vitro or animal model test systems.

V. Labeled Compounds and Assay Methods

The compounds of the present disclosure can further be useful ininvestigations of biological processes in normal and abnormal tissues.Thus, another aspect of the present invention relates to labeledcompounds of the invention (radio-labeled, fluorescent-labeled, etc.)that would be useful not only in imaging techniques but also in assays,both in vitro and in vivo, for localizing and quantitating PD-1 or PD-L1protein in tissue samples, including human, and for identifying PD-L1ligands by inhibition binding of a labeled compound. Accordingly, thepresent invention includes PD-1/PD-L1 binding assays that contain suchlabeled compounds.

The present invention further includes isotopically-labeled compounds ofthe disclosure. An “isotopically” or “radio-labeled” compound is acompound of the invention where one or more atoms are replaced orsubstituted by an atom having an atomic mass or mass number differentfrom the atomic mass or mass number typically found in nature (i.e.,naturally occurring). Suitable radionuclides that may be incorporated incompounds of the present invention include but are not limited todeuterium, ³H (also written as T for tritium), ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N,¹⁵O, ¹⁷O, ¹⁸O, ¹⁸F, ³⁵S, ³⁶Cl, ⁸²Br, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br, ¹²³I, ¹²⁴I, ¹²⁵Iand ¹³¹I. The radionuclide that is incorporated in the instantradio-labeled compounds will depend on the specific application of thatradio-labeled compound. For example, for in vitro PD-L1 protein labelingand competition assays, compounds that incorporate ³H, ¹⁴C, ⁸²Br, ¹²⁵I,¹³¹I, ³⁵S or will generally be most useful. For radio-imagingapplications ¹¹C, ¹⁸F, ¹²⁵I, ¹²³I, ¹²⁴I, ¹³¹I, ⁷⁵Br, ⁷⁶Br or ⁷⁷Br willgenerally be most useful.

It is to be understood that a “radio-labeled” or “labeled compound” is acompound that has incorporated at least one radionuclide. In someembodiments the radionuclide is selected from the group consisting of³H, ¹⁴C, ¹²⁵I, ³⁵S and ⁸²Br. In some embodiments, the compoundincorporates 1, 2, 3, 4, 5, 6, 7 or 8 deuterium atoms. Synthetic methodsfor incorporating radio-isotopes into organic compounds are known in theart.

Specifically, a labeled compound of the invention can be used in ascreening assay to identify and/or evaluate compounds. For example, anewly synthesized or identified compound (i.e., test compound) which islabeled can be evaluated for its ability to bind a PD-L1 protein bymonitoring its concentration variation when contacting with the PD-L1protein, through tracking of the labeling. For example, a test compound(labeled) can be evaluated for its ability to reduce binding of anothercompound which is known to bind to a PD-L1 protein (i.e., standardcompound). Accordingly, the ability of a test compound to compete withthe standard compound for binding to the PD-L1 protein directlycorrelates to its binding affinity. Conversely, in some other screeningassays, the standard compound is labeled and test compounds areunlabeled. Accordingly, the concentration of the labeled standardcompound is monitored in order to evaluate the competition between thestandard compound and the test compound, and the relative bindingaffinity of the test compound is thus ascertained.

VI. Kits

The present disclosure also includes pharmaceutical kits useful, e.g.,in the treatment or prevention of diseases or disorders associated withthe activity of PD-L1 including its interaction with other proteins suchas PD-1 and B7-1 (CD80), such as cancer or infections, which include oneor more containers containing a pharmaceutical composition comprising atherapeutically effective amount of a compound of Formula (I), or any ofthe embodiments thereof. Such kits can further include one or more ofvarious conventional pharmaceutical kit components, such as, e.g.,containers with one or more pharmaceutically acceptable carriers,additional containers, etc., as will be readily apparent to thoseskilled in the art. Instructions, either as inserts or as labels,indicating quantities of the components to be administered, guidelinesfor administration, and/or guidelines for mixing the components, canalso be included in the kit.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of non-criticalparameters which can be changed or modified to yield essentially thesame results. The compounds of the Examples have been found to inhibitthe activity of PD-1/PD-L1 protein/protein interaction according to atleast one assay described herein.

EXAMPLES

Experimental procedures for compounds of the invention are providedbelow. Open Access Preparative LCMS Purification of some of thecompounds prepared was performed on Waters mass directed fractionationsystems. The basic equipment setup, protocols and control software forthe operation of these systems have been described in detail inliterature. See, e.g., Blom, “Two-Pump At Column Dilution Configurationfor Preparative LC-MS”, K. Blom, J. Combi. Chem., 2002, 4, 295-301; Blomet al., “Optimizing Preparative LC-MS Configurations and Methods forParallel Synthesis Purification”, J. Combi. Chem., 2003, 5, 670-83; andBlom et al., “Preparative LC-MS Purification: Improved Compound SpecificMethod Optimization”, J. Combi. Chem., 2004, 6, 874-883.

Example 12-(2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro[1,3]thiazolo[4,5-c]pyridine

Step 1:4,4,5,5-tetramethyl-2-(2-methylbiphenyl-3-yl)-1,3,2-dioxaborolane

A mixture of 3-chloro-2-methylbiphenyl (1.44 mL, 8.08 mmol) (Aldrich,cat #361623),4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl] (6.15 g,24.2 mmol), palladium acetate (72.5 mg, 0.323 mmol), K₃PO₄ (5.14 g, 24.2mmol) and 2-(dicyclohexylphosphino)-2′,6′-dimethoxy-1,1′-biphenyl (332mg, 0.808 mmol) in 1,4-dioxane (30 mL) was degassed and stirred at r.t.for 48 h. The reaction mixture was diluted with methylene chloride,washed with saturated NaHCO₃, water and brine. The organic layer wasdried over Na₂SO₄, filtered and concentrated. The residue was purifiedby flash chromatography on a silica gel column eluting with 0 to 5%ethyl acetate in methylene chloride to give the desired product (1.60 g,68%). LCMS calculated for C₁₉H₂₄BO₂ (M+H)⁺: m/z=295.2. found 295.1.

Step 2: tert-butyl2-(2-methylbiphenyl-3-yl)-6,7-dihydro[1,3]thiazolo[4,5-c]pyridine-5(4H)-carboxylate

To a solution of tert-butyl2-bromo-6,7-dihydro[1,3]thiazolo[4,5-c]pyridine-5(4H)-carboxylate (9.9mg, 31 μmol) (Astatech, cat #27671),4,4,5,5-tetramethyl-2-(2-methylbiphenyl-3-yl)-1,3,2-dioxaborolane (10mg, 34 μmol) and sodium carbonate (8.2 mg, 77.2 μmol) in tert-butylalcohol (0.3 mL) and water (0.1 mL) was addeddichloro[1,1′-bis(dicyclohexylphosphino)ferrocene]palladium(II) (Pd-127:4.7 mg, 6.2 μmol). The mixture was purged with N₂, then heated at 110°C. for 2 h. The reaction mixture was diluted with methylene chloride,washed with saturated NaHCO₃, water and brine. The organic layer wasdried over Na₂SO₄, filtered and concentrated. The residue was used inthe next step without further purification. LC-MS calculated forC₂₄H₂₇N₂O₂S (M+H)⁺: m/z=407.2. found 407.2.

Step 3:2-(2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro[1,3]thiazolo[4,5-c]pyridine

The crude product from Step 2 was dissolved in methylene chloride (0.6mL) then treated with TFA (0.3 mL). The resulting mixture was stirred atroom temperature for 30 min before concentrated and purified byprep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product asthe TFA salt. LC-MS calculated for C₁₉H₁₉N₂S (M+H)⁺: m/z=307.2. found307.2.

Example 22-(2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine

Step 1: tert-butyl2-(2-methylbiphenyl-3-yl)-6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-5(4H)-carboxylate

This compound was prepared using similar procedures as described forExample 1, Step 2 with tert-butyl2-bromo-6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-5(4H)-carboxylate(Astatech, cat # AB1021) replacing tert-butyl2-bromo-6,7-dihydro[1,3]thiazolo[4,5-c]pyridine-5(4H)-carboxylate. Thereaction mixture was diluted with methylene chloride, washed withsaturated NaHCO₃, water and brine. The organic layer was dried overNa₂SO₄, filtered and concentrated. The residue was used in the next stepwithout further purification. LC-MS calculated for C₂₄H₂₇N₂O₂S (M+H)⁺:m/z=407.2. found 407.2.

Step 2:2-(2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine

The crude product from Step 1 was dissolved in methylene chloride (0.6mL) then treated with TFA (0.3 mL). The resulting mixture was stirred atroom temperature for 30 min before concentrated and purified byprep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product asthe TFA salt. LC-MS calculated for C₁₉H₁₉N₂S (M+H)⁺: m/z=307.2. found307.2.

Example 35-methyl-2-(2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine

Formaldehyde (37 wt. % in water, 16 μL, 0.2 mmol) was added to asolution of2-(2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine(Example 2: 15 mg, 0.049 mmol) and N,N-diisopropylethylamine (20 μL, 0.1mmol) in methylene chloride (1.0 mL), then the reaction mixture wasallowed to stir at r.t. for 5 min before sodium triacetoxyborohydride(30 mg, 0.1 mmol) was added to the reaction mixture. The resultingmixture was stirred for another 2 h then concentrated and purified byprep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product asthe TFA salt. LC-MS calculated for C₂₀H₂₁N₂S (M+H)⁺: m/z=321.2. found321.2.

Example 42-[2-(2-methylbiphenyl-3-yl)-6,7-dihydro[1,3]thiazolo[5,4-c]pyridin-5(4H)-yl]ethanol

To a solution of2-(2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine(Example 2: 5.0 mg, 16 μmol) and bromoethanol (5.7 μL, 80 μmol) inN,N-dimethylformamide (0.5 mL) was added potassium carbonate (11 mg, 80μmol). The resulting mixture was stirred at r.t. for 16 h, and thenpurified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desiredproduct as the TFA salt. LC-MS calculated for C₂₁H₂₃N₂OS (M+H)⁺:m/z=351.2. found 351.2.

Example 5(2S)-1-[2-(2-methylbiphenyl-3-yl)-6,7-dihydro[1,3]thiazolo[5,4-c]pyridin-5(4H)-yl]propan-2-ol

To a solution of2-(2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine(Example 2: 10.0 mg, 32.6 μmol) and N,N-diisopropylethylamine (11.4 μL,0.653 mmol) in methanol (1.3 mL) was added (S)-(−)-methyloxirane (TCI,Cat #:P0951: 22.9 μL, 0.326 mmol). The reaction mixture was stirred atr.t. for 12 h, then diluted with methanol then purified by prep-HPLC(pH=2, acetonitrile/water+TFA) to give the desired product as the TFAsalt. LC-MS calculated for C₂₂H₂₅N₂OS (M+H)⁺: m/z=365.2. found 365.2.

Example 62-(2-methylbiphenyl-3-yl)-5-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine

This compound was prepared using similar procedures as described forExample 3 with tetrahydro-4H-pyran-4-one (Aldrich, Cat #198242)replacing formaldehyde. The resulting mixture was purified by prep-HPLC(pH=2, acetonitrile/water+TFA) to give the desired product as the TFAsalt. LC-MS calculated for C₂₄H₂₇N₂OS (M+H)⁺: m/z=391.2. found 391.2.

Example 74-[2-(2-methylbiphenyl-3-yl)-6,7-dihydro[1,3]thiazolo[5,4-c]pyridin-5(4H)-yl]cyclohexanecarboxylicAcid

This compound was prepared using similar procedures as described forExample 3 with 4-oxocyclohexanecarboxylic acid (Aldrich, Cat #751294)replacing formaldehyde. The resulting mixture was purified by prep-HPLC(pH=2, acetonitrile/water+TFA) to give the desired product as the TFAsalt. LC-MS calculated for C₂₆H₂₉N₂O₂S (M+H)⁺: m/z=433.2. found 433.2.

Example 84-[2-(2-methylbiphenyl-3-yl)-6,7-dihydro[1,3]thiazolo[5,4-c]pyridin-5(4H)-yl]butanoicAcid

This compound was prepared using similar procedures as described forExample 3 with 4-oxobutanoic acid (Aldrich, Cat #14075) replacingformaldehyde. The resulting mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₃H₂₅N₂O₂S (M+H)⁺: m/z=393.2. found 393.2.

Example 9Trans-2-{[2-(2-methylbiphenyl-3-yl)-6,7-dihydro[1,3]thiazolo[5,4-c]pyridin-5(4H)-yl]methyl}cyclopropanecarboxylicAcid

Step 1: ethyltrans-2-{[2-(2-methylbiphenyl-3-yl)-6,7-dihydro[1,3]thiazolo[5,4-c]pyridin-5(4H)-yl]methyl}cyclopropanecarboxylate

This compound was prepared using similar procedures as described forExample 3 with trans-ethyl 2-formylcyclopropanecarboxylate (Aldrich, Cat#157279) replacing formaldehyde. The resulting mixture was concentratedto dryness and used in the next step without further purification. LC-MScalculated for C₂₆H₂₉N₂O₂S (M+H)⁺: m/z=433.2. found 433.2.

Step 2:trans-2-{[2-(2-methylbiphenyl-3-yl)-6,7-dihydro[1,3]thiazolo[5,4-c]pyridin-5(4H)-yl]methyl}cyclopropanecarboxylicAcid

The crude product in Step 1 was treated with 1 N aq. NaOH (0.5 mL) inmethanol (1.0 mL) at 50° C. and stirred for 15 h. The reaction mixturewas cooled to room temperature then purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₄H₂₅N₂O₂S (M+H)⁺: m/z=405.2. found 405.2.

Example 102-(2-methylbiphenyl-3-yl)-5-(1H-pyrazol-4-ylmethyl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine

This compound was prepared using similar procedures as described forExample 3 with 1H-pyrazole-4-carbaldehyde (Ark Pharm, Cat # AK-25836)replacing formaldehyde. The resulting mixture was purified by prep-HPLC(pH=2, acetonitrile/water+TFA) to give the desired product as the TFAsalt. LC-MS calculated for C₂₃H₂₃N₄S (M+H)⁺: m/z=387.2. found 387.2.

Example 11{4-[2-(2-methylbiphenyl-3-yl)-6,7-dihydro[1,3]thiazolo[5,4-c]pyridin-5(4H)-yl]cyclohexyl}acetonitrile

This compound was prepared using similar procedures as described forExample 3 with (4-oxocyclohexyl)acetonitrile (Ark Pharm, Cat # AK-46872)replacing formaldehyde. The resulting mixture was purified by prep-HPLC(pH=2, acetonitrile/water+TFA) to give the desired product as the TFAsalt. LC-MS calculated for C₂₇H₃₀N₃S (M+H)⁺: m/z=428.2; found 428.2.

Example 122-(2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine

Step 1: tert-butyl2-(2-methylbiphenyl-3-yl)-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate

This compound was prepared using similar procedures as described forExample 1, Step 2 with tert-butyl2-iodo-6,7-dihydropyrazolo[1,5-a]pyrazine-5(4H)-carboxylate (AurumPharmatech, cat #10451833) replacing tert-butyl2-bromo-6,7-dihydro[1,3]thiazolo[4,5-c]pyridine-5(4H)-carboxylate. Thereaction mixture was diluted with methylene chloride, washed withsaturated NaHCO₃, water and brine. The organic layer was dried overNa₂SO₄, filtered and concentrated. The residue was used in the next stepwithout further purification. LC-MS calculated for C₂₄H₂₈N₃O₂ (M+H)⁺:m/z=390.2. found 390.2.

Step 2:2-(2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine

The crude product from Step 1 was dissolved in methylene chloride (0.6mL) then treated with TFA (0.3 mL). The resulting mixture was stirred atroom temperature for 30 min before concentrated and purified byprep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product asthe TFA salt. LC-MS calculated for C₁₉H₂₀N₃ (M+H)⁺: m/z=290.2. found290.2.

Example 132-(2,3-dihydro-1,4-benzodioxin-6-yl)-6-(4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)benzonitrile

Step 1: 2-bromo-6-(2,3-dihydro-1,4-benzodioxin-6-yl)benzonitrile

To a solution of 2-bromo-6-iodobenzonitrile (207 mg, 0.674 mmol)(Astatech, cat # CL8155), 2,3-dihydro-1,4-benzodioxin-6-ylboronic acid(127 mg, 0.707 mmol) (Aldrich, cat #635995) and sodium carbonate (178mg, 1.68 mmol) in tert-butyl alcohol (3 mL) and water (1 mL) was addedPd-127 (51 mg, 67 μmol). The reaction mixture was purged with N₂, andthen heated at 90° C. for 2 h. The reaction mixture was diluted withmethylene chloride, washed with saturated NaHCO₃, water and brine. Theorganic layer was dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by flash chromatography on a silica gel columneluting with 10 to 20% ethyl acetate in hexanes to give the desiredproduct (130 mg, 61%). LCMS calculated for C₁₅H₁₁BrNO₂ (M+H)⁺:m/z=316.2. found 316.2.

Step 2:2-(2,3-dihydro-1,4-benzodioxin-6-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile

A mixture of4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl] (106 mg,0.418 mmol), 2-bromo-6-(2,3-dihydro-1,4-benzodioxin-6-yl)benzonitrile(120 mg, 0.380 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (1:1) (20 mg, 20 μmol) and potassium acetate (112mg, 1.14 mmol) in 1,4-dioxane (3 mL) was purges with nitrogen and heatedat 90° C. for 16 h. The reaction mixture was diluted with methylenechloride, washed with saturated NaHCO₃, water and brine. The organiclayer was dried over Na₂SO₄, filtered and concentrated. The residue waspurified by flash chromatography on a silica gel column eluting with 0to 50% ethyl acetate in hexanes to give the desired product (70 mg,51%). LCMS calculated for C₂₁H₂₃BNO₄ (M+H)⁺: m/z=364.2. found 364.2.

Step 3: tert-butyl2-[2-cyano-3-(2,3-dihydro-1,4-benzodioxin-6-yl)phenyl]-6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-5(4H)-carboxylate

This compound was prepared using similar procedures as described forExample 2, Step 1 with2-(2,3-dihydro-1,4-benzodioxin-6-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile(Step 2) replacing4,4,5,5-tetramethyl-2-(2-methylbiphenyl-3-yl)-1,3,2-dioxaborolane. Thereaction mixture was diluted with methylene chloride, washed withsaturated NaHCO₃, water and brine. The organic layer was dried overNa₂SO₄, filtered and concentrated. The residue was used in the next stepwithout further purification. LC-MS calculated for C₂₆H₂₆N₃O₄S (M+H)⁺:m/z=476.2. found 476.2.

Step 4:2-(2,3-dihydro-1,4-benzodioxin-6-yl)-6-(4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)benzonitrile

The crude product from Step 3 was dissolved in methylene chloride (0.6mL) then treated with TFA (0.3 mL). The resulting mixture was stirred atroom temperature for 30 min before concentrated and purified byprep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product asthe TFA salt. LC-MS calculated for C₂₁H₁₈N₃O₂S (M+H)⁺: m/z=376.2. found376.2.

Example 142-(3-methyl-4-phenylpyridin-2-yl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine

Step 1: 2-chloro-3-methyl-4-phenylpyridine

To a solution of 2-chloro-4-iodo-3-methylpyridine (303 mg, 1.20 mmol)(Aldrich, cat #724092), phenylboronic acid (160 mg, 1.32 mmol) (Aldrich,cat #78181) and sodium carbonate (317 mg, 2.99 mmol) in tert-butylalcohol (10 mL) and water (6 mL) was added Pd-127 (181 mg, 0.239 mmol).The resulting mixture was purged with N₂, and then heated at 80° C. for2 h. The reaction mixture was diluted with methylene chloride, washedwith saturated NaHCO₃, water and brine. The organic layer was dried overNa₂SO₄, filtered and concentrated. The residue was purified by flashchromatography on a silica gel column eluting with 10 to 20% ethylacetate in hexanes to give the desired product (225 mg, 92%). LCMScalculated for C₁₂H₁₁ClN (M+H)⁺: m/z=204.2. found 204.2.

Step 2: tert-butyl2-(3-methyl-4-phenylpyridin-2-yl)-6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-5(4H)-carboxylate

A solution of 2-chloro-3-methyl-4-phenylpyridine (40.0 mg, 0.196 mmol)in 1,4-dioxane (2.0 mL) was bubbled with N₂, then hexabutyldistannane(129 μL, 0.255 mmol), lithium chloride (51.6 mg, 1.22 mmol),dichloro[bis(triphenylphosphoranyl)]palladium (14 mg, 20 μmol) andtetrakis(triphenylphosphine)palladium(O) (23 mg, 20 μmol) were added insequence. The resulting mixture was heated at 90° C. for 90 min before asolution of tert-butyl2-bromo-6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-5(4H)-carboxylate (94.0mg, 0.294 mmol) in 1,4-dioxane (1.5 mL) was pumped in over 1.5 h at 95°C. The resulted mixture was stirred at the same temperature for another12 h, then cooled to room temperature, diluted with methylene chloride,washed with saturated NaHCO₃, water and brine. The organic layer wasdried over Na₂SO₄, filtered and concentrated. The residue was used inthe next step without further purification. LC-MS calculated forC₂₃H₂₆N₃O₂S (M+H)⁺: m/z=408.2. found 408.2.

Step 3:2-(3-methyl-4-phenylpyridin-2-yl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine

The crude product from Step 2 was dissolved in methylene chloride (0.6mL) then treated with TFA (0.3 mL). The resulting mixture was stirred atroom temperature for 30 min before concentrated and purified byprep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product asthe TFA salt. LC-MS calculated for C₁₈H₁₈N₃S (M+H)⁺: m/z=308.2. found308.2. ¹H NMR (600 MHz, DMSO) δ 9.35 (s, 1H), 8.56-8.50 (m, 1H),7.55-7.51 (m, 2H), 7.50-7.46 (m, 1H), 7.44-7.40 (m, 2H), 7.34 (d, J=4.8Hz, 1H), 4.52 (br, 2H), 3.54 (br, 2H), 3.09 (t, J=6.1 Hz, 2H), 2.62 (s,3H).

Example 152-[4-(3-methoxyphenyl)-3-methylpyridin-2-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine

This compound was prepared using similar procedures as described forExample 14, Step 1-3 with 3-methoxyphenylboronic acid (Aldrich, cat#441686) replacing phenylboronic acid in Step 1. The reaction mixturewas purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give thedesired product as the TFA salt. LC-MS calculated for C₁₉H₂₀N₃OS (M+H)⁺:m/z=338.2. found 338.2.

Example 162-[4-(2,3-dihydro-1,4-benzodioxin-6-yl)-3-methylpyridin-2-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine

This compound was prepared using similar procedures as described forExample 14, Step 1-3 with 2,3-dihydro-1,4-benzodioxin-6-ylboronic acid(Combi-blocks, cat # BB-8311) replacing phenylboronic acid in Step 1.The reaction mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₀H₂₀N₃O₂S (M+H)⁺: m/z=366.2. found 366.2.

Example 172-(2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine

Step 1: 3-bromo-2-methylbiphenyl

This compound was prepared using similar procedures as described forExample 13, Step 1 with 1-bromo-3-iodo-2-methylbenzene (Oakwood, cat#037475) replacing 2-bromo-6-iodobenzonitrile, and phenylboronic acidreplacing 2,3-dihydro-1,4-benzodioxin-6-ylboronic acid. The reactionmixture was diluted with methylene chloride, washed with saturatedNaHCO₃, water and brine. The organic layer was dried over Na₂SO₄,filtered and concentrated. The residue was purified by flashchromatography on a silica gel column eluting with 0 to 5% ethyl acetatein hexanes to give the desired product.

Step 2: tert-butyl2-(2-methylbiphenyl-3-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

To a mixture of 3-bromo-2-methylbiphenyl (100 mg, 0.405 mmol),tert-butyl 1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate(Ark Pharm, Cat # AK-24984: 180 mg, 0.81 mmol),(2′-aminobiphenyl-2-yl)(chloro)[dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphoranyl]palladium(30.9 mg, 39.7 μmol) (RuPhos G2, Aldrich, cat #753246) in 1,4-dioxane(1.1 mL) was added sodium tert-butoxide (76.4 mg, 0.795 mmol). Theresulting mixture was heated at 110° C. under the atmosphere of N₂ for15 h, then diluted with methylene chloride, washed with saturatedNaHCO₃, water and brine. The organic layer was dried over Na₂SO₄,filtered and concentrated. The residue was used in the next step withoutfurther purification. LC-MS calculated for C₂₄H₂₈N₃O₂ (M+H)⁺: m/z=390.2.found 390.2.

Step 3:2-(2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine

The crude product from Step 2 was dissolved in methylene chloride (0.6mL) then treated with TFA (0.3 mL). The resulting mixture was stirred atroom temperature for 30 min before concentrated and purified byprep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product asthe TFA salt. LC-MS calculated for C₁₉H₂₀N₃ (M+H)⁺: m/z=290.2. found290.2.

Example 182-(2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine

Step 1: tert-butyl2-(2-methylbiphenyl-3-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate

This compound was prepared using similar procedures as described forExample 17, Step 2 with tert-butyl1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine-6-carboxylate (Ark Pharm,cat # AK-39955) replacing tert-butyl1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine-5-carboxylate. Theresulting mixture was diluted with methylene chloride, washed withsaturated NaHCO₃, water and brine. The organic layer was dried overNa₂SO₄, filtered and concentrated. The residue was used in the next stepwithout further purification. LC-MS calculated for C₂₄H₂₈N₃O₂ (M+H)⁺:m/z=390.2. found 390.2.

Step 2:2-(2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine

The crude product from Step 1 was dissolved in methylene chloride (0.6mL) then treated with TFA (0.3 mL). The resulting mixture was stirred atroom temperature for 30 min before concentrated and purified byprep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product asthe TFA salt. LC-MS calculated for C₁₉H₂₀N₃ (M+H)⁺: m/z=290.2. found290.2.

Example 197,7-dimethyl-2-(2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine

Step 1: tert-butyl 5-bromo-3,3-dimethyl-4-oxopiperidine-1-carboxylate

To a solution of tert-butyl 3,3-dimethyl-4-oxopiperidine-1-carboxylate(107 mg, 469 μmol) (Combi-blocks, cat # QA-1430) in chloroform (2.0 mL)was added bromine (24.2 μL, 469 μmol) in chloroform (0.5 mL) at 0° C.After stirred at the same temperature for 15 min, it was allowed to warmup to r.t. and stirred for another 30 min. The resulted mixture wasconcentrated to dryness and used in the next step without furtherpurification. LC-MS calculated for C₁₂H₂₁BrNO₃ (M+H)⁺: m/z=306.2. found306.2.

Step 2: tert-butyl2-amino-7,7-dimethyl-6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-5(4H)-carboxylate

To a solution of above crude product in ethanol (0.5 mL) was addedthiourea (53.5 mg, 703 μmol). The resulted mixture was heated at 80° C.for 3 h then concentrated to dryness and used in the next step withoutfurther purification. LC-MS calculated for C₁₃H₂₂N₃O₂S (M+H)⁺:m/z=284.2. found 284.2.

Step 3: tert-butyl2-bromo-7,7-dimethyl-6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-5(4H)-carboxylate

To a solution of the crude product from Step 2 in acetonitrile (1.0 mL)was added tert-butyl nitrite (94.8 μL, 797 μmol) and copper(II) bromide(157 mg, 703 μmol). After the reaction mixture was stirred for 3 h, itwas diluted with methylene chloride and washed over water. The organiclayer was dried over Na₂SO₄, filtered and concentrated. The residue wasused in the next step without further purification. LC-MS calculated forC₁₃H₂₀BrN₂O₂S (M+H)⁺: m/z=347.2. found 347.2.

Step 4: tert-butyl7,7-dimethyl-2-(2-methylbiphenyl-3-yl)-6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-5(4H)-carboxylate

This compound was prepared using similar procedures as described forExample 1, Step 2 with tert-butyl2-bromo-7,7-dimethyl-6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-5(4H)-carboxylate(Step 3) replacing tert-butyl2-bromo-6,7-dihydro[1,3]thiazolo[4,5-c]pyridine-5(4H)-carboxylate. Thereaction mixture was diluted with methylene chloride, washed withsaturated NaHCO₃, water and brine. The organic layer was dried overNa₂SO₄, filtered and concentrated. The residue was used in the next stepwithout further purification. LC-MS calculated for C₂₆H₃₁N₂O₂S (M+H)⁺:m/z=435.2. found 435.2.

Step 5:7,7-dimethyl-2-(2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine

The crude product from Step 4 was dissolved in methylene chloride (0.6mL) then treated with TFA (0.3 mL). The resulting mixture was stirred atroom temperature for 30 min before concentrated and purified byprep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product asthe TFA salt. LC-MS calculated for C₂₁H₂₃N₂S (M+H)⁺: m/z=335.2. found335.2.

Example 202-(2-methylbiphenyl-3-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine

Step 1: 1-(2-methylbiphenyl-3-yl)ethanone

To a solution of 1-(3-bromo-2-methylphenyl)ethanone (500 mg, 2.35 mmol)(Astatech, cat # CL9266), phenylboronic acid (300 mg, 2.46 mmol) andsodium carbonate (622 mg, 5.87 mmol) in tert-butyl alcohol (10 mL) andwater (4 mL) was added Pd-127 (178 mg, 235 μmol). The resulted mixturewas heated at 105° C. for 2 h, and then was diluted with methylenechloride, washed with saturated NaHCO₃, water and brine. The organiclayer was dried over Na₂SO₄, filtered and concentrated. The residue waspurified by flash chromatography on a silica gel column eluting with 0to 50% ethyl acetate in hexanes to give the desired product (400 mg,80%). LC-MS calculated for C₁₅H₁₅O (M+H)⁺: m/z=211.2. found 211.2.

Step 2: 2-bromo-1-(2-methylbiphenyl-3-yl)ethanone

To a solution of 1-(2-methylbiphenyl-3-yl)ethanone (1.25 g, 5.94 mmol)in ethyl acetate (30 mL) was added copper(II) bromide (5.3 g, 24 mmol)then stirred at 80° C. for 2 hours, then it was filtered andconcentrated to dryness under reduced pressure. The residue was purifiedby flash chromatography on a silica gel column eluting with 0 to 50%ethyl acetate in hexanes to give the desired product (1.50 g, 87%).LC-MS calculated for C₁₅H₁₄BrO (M+H)⁺: m/z=289.2. found 289.2.

Step 3: 2-(2-methylbiphenyl-3-yl)imidazo[1,2-a]pyrazine

A solution of 2-bromo-1-(2-methylbiphenyl-3-yl)ethanone (20 mg, 69μmol), aminopyrazine (9.87 mg, 104 μmol) in acetonitrile (0.4 mL) washeated at 100° C. for 2 h, then it was concentrated to dryness underreduced pressure. The residue was used in the next step without furtherpurification. LC-MS calculated for C₁₉H₁₆N₃ (M+H)⁺: m/z=286.2. found286.2.

Step 4:2-(2-methylbiphenyl-3-yl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine

To the solution of the crude product from Step 3 in methanol (2.0 mL)was added Pd/C (10 mg) and the resulting mixture was stirred at r.t. for4 h under an atmosphere of H2. The resulting mixture was filtered andpurified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desiredproduct as the TFA salt. LC-MS calculated for C₁₉H₂₀N₃ (M+H)⁺:m/z=290.2. found 290.2.

Example 212-(2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine

Step 1: 2-methylbiphenyl-3-carbaldehyde

To a solution of (2-methylbiphenyl-3-yl)methanol (TCI, Cat #: H0777:4.12 g, 20.8 mmol) in methylene chloride (60 mL) was slowly addedDess-Martin periodinane (9.25 g, 21.8 mmol). The resulting mixture wasstirred at r.t. for 30 min, and then washed with saturated NaHCO₃, waterand brine. The organic layer was dried over Na₂SO₄, filtered andconcentrated. The residue was purified by flash chromatography on asilica gel column eluting with 0 to 30% ethyl acetate in hexanes to givethe desired product (3.30 g, 80%). LC-MS calculated for C₁₄H₁₃O (M+H)⁺:m/z=197.2. found 197.2.

Step 2: 2-(2-methylbiphenyl-3-yl)-1H-imidazo[4,5-c]pyridine

To a solution of pyridine-3,4-diamine (15 mg, 0.14 mmol) and2-methylbiphenyl-3-carbaldehyde (30 mg, 0.15 mmol) in methanol (0.69 mL)was added catalytic amount of zinc triflate (5 mg), then heated at 70°C. for 36 h. The resulting mixture was filtered and purified byprep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product asthe TFA salt. LC-MS calculated for C₁₉H₁₆N₃ (M+H)⁺: m/z=286.2. found286.2.

Step 3:5-benzyl-2-(2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine

To a solution of 2-(2-methylbiphenyl-3-yl)-1H-imidazo[4,5-c]pyridine (10mg, TFA salt) in DMF (0.3 mL) was added benzylbromide (10 μL) and DIPEA(10 μL). The resulting mixture was heated at 100° C. for 2 h, thenconcentrated to dryness. The crude mixture was dissolved in methanol(2.0 mL) and NaBH₄ (10 mg) was added at r.t. The resulting mixture wasstirred for 30 min and purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₆H₂₆N₃ (M+H)⁺: m/z=380.2. found 380.2.

Step 4:2-(2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine

To a solution of5-benzyl-2-(2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine(5 mg, TFA salt) in methanol (2.0 mL) was added Pd/C (10 mg) and stirredat r.t. for 4 h under an atmosphere of H₂. The resulting mixture wasfiltered and purified by prep-HPLC (pH=2, acetonitrile/water+TFA) togive the desired product as the TFA salt. LC-MS calculated for C₁₉H₂₀N₃(M+H)⁺: m/z=290.2. found 290.2.

Example 222-(2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro[1,3]oxazolo[5,4-c]pyridine

Step 1: 2-(2-methylbiphenyl-3-yl)[1,3]oxazolo[5,4-c]pyridine

To a mixture of 2-methylbiphenyl-3-carboxylic acid (100 mg, 471 μmol)(Combi-Blocks, cat # YA-8643) and triethylamine (65.7 μL, 471 μmol) inmethylene chloride (2.0 mL) was added cyanuric chloride (28.9 mg, 157μmol). The resulting mixture was heated at 60° C. for 20 min then4-aminopyridin-3-ol (51.9 mg, 471 μmol) was added. The resulting mixturewas heated at the same temperature for 18 h then cooled to roomtemperature and concentrated. The residue was purified by prep-HPLC(pH=2, acetonitrile/water+TFA) to give the desired product as the TFAsalt. LC-MS calculated for C₁₉H₁₅N₂O (M+H)⁺: m/z=287.2. found 287.2.

Step 2:5-benzyl-2-(2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro[1,3]oxazolo[5,4-c]pyridine

This compound was prepared using similar procedures as described forExample 21, Step 3 with2-(2-methylbiphenyl-3-yl)[1,3]oxazolo[5,4-c]pyridine (Step 1) replacing2-(2-methylbiphenyl-3-yl)-1H-imidazo[4,5-c]pyridine. The resultingmixture was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to givethe desired product as the TFA salt. LC-MS calculated for C₂₆H₂₅N₂O(M+H)⁺: m/z=381.2. found 381.3.

Step 3:2-(2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro[1,3]oxazolo[5,4-c]pyridine

This compound was prepared using similar procedures as described forExample 21, Step 4 with5-benzyl-2-(2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro[1,3]oxazolo[5,4-c]pyridine(Step 2) replacing5-benzyl-2-(2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine.The resulting mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₁₉H₁₉N₂O (M+H)⁺: m/z=291.2. found 291.2.

Example 232-(2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro[1,3]oxazolo[4,5-c]pyridine

This compound was prepared using similar procedures as described forExample 22 with 3-aminopyridin-4-ol replacing 4-aminopyridin-3-ol inStep 1. The reaction mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₁₉H₁₉N₂O (M+H)⁺: m/z=291.2. found 291.2.

Example 245-methyl-2-(2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro[1,3]oxazolo[4,5-c]pyridine

This compound was prepared using similar procedures as described forExample 3 with2-(2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro[1,3]oxazolo[4,5-c]pyridine(Example 23) replacing2-(2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine.The resulting mixture was purified by prep-HPLC (pH=2,acetonitrile/water+TFA) to give the desired product as the TFA salt.LC-MS calculated for C₂₀H₂₁N₂O (M+H)⁺: m/z=305.2. found 305.2.

Example 252-(2-methylbiphenyl-3-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyrazine

Step 1: ethyl [(pyrazin-2-ylamino)carbonothioyl]carbamate

To a solution of aminopyrazine (200 mg, 2.10 mmol) in 1,4-dioxane (10mL) was added ethoxycarbonyl isothiocyanate (273 μL, 2.42 mmol). Thereaction mixture was stirred at r.t. for 15 h. The resulted mixture wasconcentrated to dryness and used in the next step without furtherpurification. LC-MS calculated for C₈H₁₁N₄O₂S (M+H)⁺: m/z=227.2. found227.2.

Step 2: [1,2,4]triazolo[1,5-a]pyrazin-2-amine

To a solution of the crude product from Step 1 in methanol (7.0 mL) andethanol (7.0 mL) was added hydroxyaminehydrochoride (438 mg, 6.31 mmol)and N,N-diisopropylethylamine (733 μL, 4.20 mmol). The resulting mixturewas heated at 75° C. for 7 h. After cooled to room temperature, theprecipitated product (yellow solid) was filtered and washed with smallamount of methanol. LC-MS calculated for C₅H₆N₅ (M+H)⁺: m/z=136.2. found136.2.

Step 3: 2-bromo[1,2,4]triazolo[1,5-a]pyrazine

This compound was prepared using similar procedures as described forExample 19, Step 3 with [1,2,4]triazolo[1,5-a]pyrazin-2-amine (Step 2)replacing tert-butyl2-amino-7,7-dimethyl-6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-5(4H)-carboxylate.After stirred for 3 h, the reaction mixture was diluted with methylenechloride and washed over water. The organic layer was dried over Na₂SO₄,filtered and concentrated. The residue was used in the next step withoutfurther purification. LC-MS calculated for C₅H₄BrN₄ (M+H)⁺: m/z=199.2.found 199.2.

Step 4: 2-(2-methylbiphenyl-3-yl)[1,2,4]triazolo[1,5-a]pyrazine

This compound was prepared using similar procedures as described forExample 1, Step 2 with 2-bromo[1,2,4]triazolo[1,5-a]pyrazine (Step 3)replacing tert-butyl2-bromo-6,7-dihydro[1,3]thiazolo[4,5-c]pyridine-5(4H)-carboxylate. Thereaction mixture was diluted with methylene chloride, washed withsaturated NaHCO₃, water and brine. The organic layer was dried overNa₂SO₄, filtered and concentrated. The residue was used in the next stepwithout further purification. LC-MS calculated for C₁₈H₁₅N₄ (M+H)⁺:m/z=287.2. found 287.2.

Step 5:2-(2-methylbiphenyl-3-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyrazine

The crude product from Step 4 was dissolved in methanol (1.0 mL) thentreated with LiBH₄ (10 mg) at 50° C. for 30 min. The resulting mixturewas quenched with TFA before concentrated and purified by prep-HPLC(pH=2, acetonitrile/water+TFA) to give the desired product as the TFAsalt. LC-MS calculated for C₁₈H₁₉N₄ (M+H)⁺: m/z=291.2. found 291.2.

Example 262-[2-(2,3-dihydro-1,4-benzodioxin-6-yl)-3-methylpyridin-4-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine

Step 1: (2-chloro-3-methylpyridin-4-yl)boronic Acid

A mixture of 2-chloro-4-iodo-3-methylpyridine (250 mg, 986 μmol)(AstaTech, cat #22441) and boric acid, trimethyl ester (224 μL, 1.97mmol) in tetrahydrofuran (5.0 mL) was added 2.5 M n-butyllithium inhexanes (789 μL, 1.97 mmol) dropwise at −78° C. The reaction mixture wasallowed to warm up to r.t. after 90 min and stirred for another 30 min.The resulting mixture was concentrated and acetonitrile (5 mL) wasadded. The resulting suspension was filtered through celite thenconcentrated to give the desired product. LCMS calculated for C₆H₈BClNO₂(M+H)⁺: m/z=172.2. found 172.2.

Step 2: tert-butyl2-(2-chloro-3-methylpyridin-4-yl)-6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-5(4H)-carboxylate

To a solution of (2-chloro-3-methylpyridin-4-yl)boronic acid (Example26, Step 1: 170 mg, 1.0 mmol), tert-butyl2-bromo-6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-5(4H)-carboxylate(AstaTech, cat # AB1021: 320 mg, 1.0 mmol) and sodium carbonate (314 mg,2.96 mmol) in tert-butyl alcohol (10 mL) and water (5 mL) was addedPd-127 (75 mg, 0.10 mmol). The resulting mixture was purged with N₂,then heated at 105° C. for 2 h. The reaction mixture was diluted withmethylene chloride, washed with saturated NaHCO₃, water and brine. Theorganic layer was dried over Na₂SO₄, filtered and concentrated. Theresidue was used in the next step without further purification. LC-MScalculated for C₁₇H₂₁ClN₃O₂S (M+H)⁺: m/z=366.1. found 366.2.

Step 3: tert-butyl2-[2-(2,3-dihydro-1,4-benzodioxin-6-yl)-3-methylpyridin-4-yl]-6,7-dihydro[1,3]thiazolo[5,4-e]pyridine-5(4H)-carboxylate

To a solution of 2,3-dihydro-1,4-benzodioxin-6-ylboronic acid(Combi-blocks, Cat # BB-8311: 36 mg, 0.20 mmol), tert-butyl2-bromo-6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-5(4H)-carboxylate(Example 26, Step 2: 32 mg, 0.10 mmol) and sodium carbonate (31 mg, 0.30mmol) in tert-butyl alcohol (1.0 mL) and water (0.6 mL) was added Pd-127(15 mg, 0.020 mmol). The resulting mixture was purged with N₂, thenheated at 105° C. for 1.5 h. The reaction mixture was diluted withmethylene chloride, washed with saturated NaHCO₃, water and brine. Theorganic layer was dried over Na₂SO₄, filtered and concentrated. Theresidue was used in the next step without further purification. LC-MScalculated for C₂₅H₂₈N₃O₄S (M+H)⁺: m/z=466.1. found 466.2.

Step 4:2-[2-(2,3-dihydro-1,4-benzodioxin-6-yl)-3-methylpyridin-4-yl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine

The crude product from Step 3 was dissolved in methylene chloride (0.6mL) then treated with TFA (0.3 mL). The resulting mixture was stirred atroom temperature for 30 min then concentrated and purified by prep-HPLC(pH=2, acetonitrile/water+TFA) to give the desired product as the TFAsalt. LC-MS calculated for C₂₀H₂₀N₃O₂S (M+H)⁺: m/z=366.2. found 366.2.

Example 272-[2-methyl-3-(3-thienyl)phenyl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine

Step 1: tert-butyl2-(3-chloro-2-methylphenyl)-6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-5(4H)-carboxylate

To a solution of (3-chloro-2-methylphenyl)boronic acid (Combi-blocks,cat # BB-2035: 64 mg, 0.38 mmol), tert-butyl2-bromo-6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-5(4H)-carboxylate(AstaTech, cat # AB1021: 100 mg, 0.31 mmol) and sodium carbonate (100mg, 0.94 mmol) in tert-butyl alcohol (3.2 mL) and water (2 mL) was addedPd-127 (47 mg, 0.063 mmol). The resulting mixture was purged with N₂,then heated at 105° C. for 2 h. The reaction mixture was diluted withmethylene chloride, washed with saturated NaHCO₃, water and brine. Theorganic layer was dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by flash chromatography on a silica gel columneluting with 0 to 40% ethyl acetate in hexanes to give the desiredproduct (114 mg, 83%). LC-MS calculated for C₁₈H₂₂ClN₂O₂S (M+H)⁺:m/z=365.1. found 365.2.

Step 2: tert-butyl2-[2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-5(4H)-carboxylate

A mixture of tert-butyl2-(3-chloro-2-methylphenyl)-6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-5(4H)-carboxylate(Example 26, Step 1: 95 mg, 0.26 mmol),4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl] (200 mg,0.78 mmol), palladium acetate (2.5 mg, 0.014 mmol), K₃PO₄ (170 mg, 0.78mmol) and 2-(dicyclohexylphosphino)-2′,6′-dimethoxy-1,1′-biphenyl (11mg, 0.026 mmol) in 1,4-dioxane (1 mL) was degassed and stirred at r.t.for 3 d. The reaction mixture was diluted with methylene chloride,washed with saturated NaHCO₃, water and brine. The organic layer wasdried over Na₂SO₄, filtered and concentrated. The residue was purifiedby flash chromatography on a silica gel column eluting with 0 to 5%ethyl acetate in methylene chloride to give the desired product (108 mg,90%). LC-MS calculated for C₂₄H₃₄BN₂O₄S (M+H)⁺: m/z=457.2. found 457.2.

Step 3: tert-butyl2-[2-methyl-3-(3-thienyl)phenyl]-6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-5(4H)-carboxylate

To a solution of tert-butyl2-[2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-5(4H)-carboxylate(Example 26, Step 2: 15 mg, 0.033 mmol), thiophene, 3-bromo- (6.2 μL,0.066 mmol) and sodium carbonate (8.7 mg, 0.082 mmol) in tert-butylalcohol (0.3 mL) and water (0.2 mL) was added Pd-127 (5.0 mg, 0.0066mmol). The resulting mixture was purged with N₂, then heated at 105° C.for 1.5 h. The reaction mixture was diluted with methylene chloride,washed with saturated NaHCO₃, water and brine. The organic layer wasdried over Na₂SO₄, filtered and concentrated. The residue was used inthe next step without further purification. LC-MS calculated forC₂₂H₂₅N₂O₂S₂ (M+H)⁺: m/z=413.1. found 413.2.

Step 4:2-[2-methyl-3-(3-thienyl)phenyl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine

The crude product from Step 3 was dissolved in methylene chloride (0.6mL) then treated with TFA (0.3 mL). The resulting mixture was stirred atroom temperature for 30 min then concentrated and purified by prep-HPLC(pH=2, acetonitrile/water+TFA) to give the desired product as the TFAsalt. LC-MS calculated for C₁₇H₁₇N₂S₂ (M+H)⁺: m/z=313.1. found 313.2.

Example 282-(3′-methoxy-2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine

This compound was prepared using similar procedures as described forExample 27, Step 1-4 with 1-bromo-3-methoxybenzene replacing3-bromothiophene in Step 3. The reaction mixture was purified byprep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product asthe TFA salt. LC-MS calculated for C₂₀H₂₁N₂OS (M+H)⁺: m/z=337.2. found337.2.

Example 292-[3-(3,6-dihydro-2H-pyran-4-yl)-2-methylphenyl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine

This compound was prepared using similar procedures as described forExample 27, Step 1-4 with 4-bromo-3,6-dihydro-2H-pyran (Combi-blocks,cat # OT-0686) replacing 3-bromothiophene in Step 3. The reactionmixture was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to givethe desired product as the TFA salt. LC-MS calculated for C₁₈H₂₁N₂OS(M+H)⁺: m/z=313.2. found 313.2.

Example 302-[3-(2-methoxypyridin-4-yl)-2-methylphenyl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine

This compound was prepared using similar procedures as described forExample 27, Step 1-4 with 4-bromo-2-methoxypyridine (Ark Pharm, cat #AK-47404) replacing 3-bromothiophene in Step 3. The reaction mixturepurified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desiredproduct as the TFA salt. LC-MS calculated for C₁₉H₂₀N₃OS (M+H)⁺:m/z=338.2. found 338.2.

Example 312-[3-(5-fluoropyridin-2-yl)-2-methylphenyl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine

This compound was prepared using similar procedures as described forExample 27, Step 1-4 with 2-bromo-5-fluoropyridine (Aldrich, cat#595675) replacing 3-bromothiophene in Step 3. The reaction mixture waspurified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desiredproduct as the TFA salt. LC-MS calculated for C₁₈H₁₇FN₃S (M+H)⁺:m/z=326.2. found 326.2.

Example 322-(3-cyclohex-1-en-1-yl-2-methylphenyl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine

This compound was prepared using similar procedures as described forExample 27 with 1-bromocyclohexene (Combi-blocks, cat # OT-0350)replacing 3-bromothiophene in Step 3. The reaction mixture was purifiedby prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired productas the TFA salt. LC-MS calculated for C₁₉H₂₃N₂S (M+H)⁺: m/z=311.2. found311.2.

Example 332-(3′-ethoxy-2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine

This compound was prepared using similar procedures as described forExample 27 with 1-bromo-3-ethoxybenzene (Aldrich, cat #453250) replacing3-bromothiophene in Step 3. The reaction mixture was purified byprep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product asthe TFA salt. LC-MS calculated for C₂₁H₂₃N₂OS (M+H)⁺: m/z=351.2. found351.2.

Example 342-(3′,5′-dimethoxy-2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine

This compound was prepared using similar procedures as described forExample 27 with 3,5-dimethoxybromobenzene (Aldrich, cat #569313)replacing 3-bromothiophene in Step 3. The reaction mixture was purifiedby prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired productas the TFA salt. LC-MS calculated for C₂₁H₂₃N₂O₂S (M+H)⁺: m/z=367.2.found 367.2.

Example 354-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)nicotinonitrile

This compound was prepared using similar procedures as described forExample 16 with 2-chloro-4-iodonicotinonitrile (Aurum Pharmatech, cat #A-6061) replacing 2-chloro-4-iodo-3-methylpyridine. The reaction mixturewas purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give thedesired product as the TFA salt. LC-MS calculated for C₂₀H₁₇N₄O₂S(M+H)⁺: m/z=377.2. found 377.2.

Example 362-{[2′-methyl-3′-(4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)biphenyl-3-yl]oxy}ethanol

Step 1: 2-(3-bromophenoxy)ethanol

To a solution of 3-bromophenol (100 mg, 0.58 mmol) and 2-bromoethanol(36 mg, 0.29 mmol) in methanol (1 mL) was added potassium carbonate (80mg, 0.58 mmol). The reaction mixture was heated at 55° C. for 4 h, andthen diluted with methylene chloride, washed with water and brine. Theorganic layer was dried over Na₂SO₄, filtered and concentrated. Theresidue was used in the next step without further purification.

Step 2:2-{[2′-methyl-3′-(4,5,6,7-tetrahydro[1,3]thiazolo[5,4-e]pyridin-2-yl)biphenyl-3-yl]oxy}ethanol

This compound was prepared using similar procedures as described forExample 27, Steps 1-4 with 2-(3-bromophenoxy)ethanol (Step 1) replacing3-bromothiophene in Step 3. The reaction mixture was purified byprep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product asthe TFA salt. LC-MS calculated for C₂₁H₂₃N₂O₂S (M+H)⁺: m/z=367.2. found367.2.

Example 372-(2′,6′-difluoro-3′,5′-dimethoxy-2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine

Step 1: 2,4-difluoro-3-iodo-1,5-dimethoxybenzene

To a stirred slurry of 2,6-difluoro-3,5-dimethoxyaniline (500 mg, 2.64mmol) in 6.0 M hydrogen chloride in water (4 mL, 24 mmol) was added asolution of sodium nitrite (191 mg, 2.78 mmol) in water (1 mL) dropwiseover 15 min at 0° C. After stirring the resulting mixture at 0° C. foranother 15 min, a solution of potassium iodide (1.8 g, 10. mmol) inwater (2 mL) was slowly added to the resulting orange-red slurry at 0°C. with vigorous stirring. After completion of the addition, thereaction mixture was allowed to warm up to r.t. for 1 hour. The solidwas collected by filtration, washed with water and dried under vacuum.570 mg solid was collected and used directly in the next step.

Step 2:2-(2′,6′-difluoro-3′,5′-dimethoxy-2-methylbiphenyl-3-yl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine

This compound was prepared using similar procedures as described forExample 27,

Step 1-4 with 2,4-difluoro-3-iodo-1,5-dimethoxybenzene (Step 1)replacing 3-bromothiophene in Step 3. The reaction mixture was purifiedby prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired productas the TFA salt. LC-MS calculated for C₂₁H₂₁F₂N₂O₂S (M+H)⁺: m/z=403.2.found 403.2.

Example 382′-methyl-3′-(4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)biphenyl-3-carboxamide

Step 1: tert-butyl2-[3′-(aminocarbonyl)-2-methylbiphenyl-3-yl]-6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-5(4H)-carboxylate

This compound was prepared using similar procedures as described forExample 27, Step 3 with 3-bromobenzoic acid nitrile (Aldrich, cat #B58202) replacing 3-bromothiophene. The reaction mixture was dilutedwith methylene chloride, washed with saturated NaHCO₃, water and brine.The organic layer was dried over Na₂SO₄, filtered and concentrated. Theresidue was used in the next step without further purification. LC-MScalculated for C₂₅H₂₈N₃O₃S (M+H)⁺: m/z=450.2. found 450.2.

Step 2:2′-methyl-3′-(4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)biphenyl-3-carboxamide

The crude product from Step 1 was dissolved in methylene chloride (0.6mL) then treated with TFA (0.3 mL). The resulting mixture was stirred atroom temperature for 30 min then concentrated and purified by prep-HPLC(pH=2, acetonitrile/water+TFA) to give the desired product as the TFAsalt. LC-MS calculated for C₂₀H₂₀N₃OS (M+H)⁺: m/z=350.2. found 350.2.

Example 39 2-[2′-methyl-3(4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)biphenyl-3-yl]acetamide

Step 1: tert-butyl2-[3′-(2-amino-2-oxoethyl)-2-methylbiphenyl-3-yl]-6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-5(4H)-carboxylate

This compound was prepared using similar procedures as described forExample 27, Step 3 with (3-bromophenyl)acetonitrile (Aldrich, cat#260088) replacing 3-bromothiophene. The reaction mixture was dilutedwith methylene chloride, washed with saturated NaHCO₃, water and brine.The organic layer was dried over Na₂SO₄, filtered and concentrated. Theresidue was used in the next step without further purification. LC-MScalculated for C₂₆H₃₀N₃O₃S (M+H)⁺: m/z=464.2. found 464.2.

Step 2:2-[2′-methyl-3′-(4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)biphenyl-3-yl]acetamide

The crude product from Step 1 was dissolved in methylene chloride (0.6mL) then treated with TFA (0.3 mL). The resulting mixture was stirred atroom temperature for 30 min then concentrated and purified by prep-HPLC(pH=2, acetonitrile/water+TFA) to give the desired product as the TFAsalt. LC-MS calculated for C₂₁H₂₂N₃OS (M+H)⁺: m/z=364.2. found 364.2. ¹HNMR (500 MHz, CD₃OD) δ 7.57-7.53 (m, 1H), 7.43-7.38 (m, 1H), 7.38-7.32(m, 3H), 7.31-7.27 (m, 1H), 7.24-7.20 (m, 1H), 4.62-4.54 (m, 2H),3.71-3.64 (m, 2H), 3.58 (s, 2H), 3.21 (t, J=6.2 Hz, 2H), 2.31 (s, 3H).

Example 402-[2-methyl-3-(1-methyl-1H-indazol-4-yl)phenyl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine

Step 1: 4-bromo-1-methyl-1H-indazole

To a solution of 4-bromo-1H-indazole (Aldrich, cat #776610: 100. mg,0.508 mmol) in acetone (2.5 mL) was added potassium hydroxide (85.4 mg,1.52 mmol). The resulting mixture was stirred at room temperature for 10min then methyl iodide (63.2 μL, 1.02 mmol) was added. The mixture wasstirred at room temperature overnight then concentrated to give amixture of 4-bromo-2-methyl-2H-indazole and4-bromo-1-methyl-1H-indazole, which was used in the next step withoutfurther purification. LC-MS calculated for C₈H₈BrN₂ (M+H)⁺: m/z=211.0.found 211.1.

Step 2:2-[2-methyl-3-(1-methyl-1H-indazol-4-yl)phenyl]-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridine

This compound was prepared using similar procedures as described forExample 27, Step 1-4 with 4-bromo-1-methyl-1H-indazole (crude productfrom Step 1) replacing 3-bromothiophene in Step 3. The reaction mixturewas purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give thedesired product as the TFA salt. LC-MS calculated for C₂₁H₂₁N₄S (M+H)⁺:m/z=361.1. found 361.2. ¹H NMR (600 MHz, CD₃OD) δ 7.69-7.67 (m, 1H),7.66-7.63 (m, 1H), 7.61-7.58 (m, 1H), 7.55-7.51 (m, 1H), 7.46-7.41 (m,2H), 7.08 (d, J=6.9 Hz, 1H), 4.62-4.56 (m, 2H), 4.12 (s, 3H), 3.67 (t,J=6.2 Hz, 2H), 3.22 (t, J=6.2 Hz, 2H), 2.23 (s, 3H).

Example A. PD-1/PD-L1 Homogeneous Time-Resolved Fluorescence (HTRF)Binding Assay

The assays were conducted in a standard black 384-well polystyrene platewith a final volume of 20 μL. Inhibitors were first serially diluted inDMSO and then added to the plate wells before the addition of otherreaction components. The final concentration of DMSO in the assay was1%. The assays were carried out at 25° C. in the PBS buffer (pH 7.4)with 0.05% Tween-20 and 0.1% BSA. Recombinant human PD-L1 protein(19-238) with a His-tag at the C-terminus was purchased fromAcroBiosystems (PD1-H5229). Recombinant human PD-1 protein (25-167) withFc tag at the C-terminus was also purchased from AcroBiosystems(PD1-H5257). PD-L1 and PD-1 proteins were diluted in the assay bufferand 10 μL was added to the plate well. Plates were centrifuged andproteins were preincubated with inhibitors for 40 minutes. Theincubation was followed by the addition of 10 μL of HTRF detectionbuffer supplemented with Europium cryptate-labeled anti-human IgG(PerkinElmer-AD0212) specific for Fc and anti-His antibody conjugated toSureLight®-Allophycocyanin (APC, PerkinElmer-AD0059H). Aftercentrifugation, the plate was incubated at 25° C. for 60 min beforereading on a PHERAstar FS plate reader (665 nm/620 nm ratio). Finalconcentrations in the assay were—3 nM PD1, 10 nM PD-L1, 1 nM europiumanti-human IgG and 20 nM anti-His-Allophycocyanin. IC₅₀ determinationwas performed by fitting the curve of percent control activity versusthe log of the inhibitor concentration using the GraphPad Prism 5.0software.

Compounds of the present disclosure, as exemplified in Examples 1-40,showed IC₅₀ values in the following ranges: +=IC₅₀≤100 nM; ++=100nM<IC₅₀≤500 nM; +++=500 nM<IC₅₀≤10000 nM

Data obtained for the Example compounds using the PD-1/PD-L1 homogenoustime-resolved fluorescence (HTRF) binding assay described in Example Ais provided in Table 1.

TABLE 1 PD-1/PD-L1 HTRF Example IC₅₀ (nM) 1 +++ 2 + 3 + 4 + 5 + 6 ++ 7 +8 + 9 ++ 10 ++ 11 ++ 12 ++ 13 + 14 + 15 + 16 + 17 ++ 18 + 19 +++ 20 +++21 +++ 22 + 23 + 24 + 25 ++ 26 +++ 27 ++ 28 + 29 +++ 30 ++ 31 +++ 32 +33 + 34 + 35 ++ 36 ++ 37 + 38 + 39 + 40 +

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference, including withoutlimitation all patent, patent applications, and publications, cited inthe present application is incorporated herein by reference in itsentirety.

1. A compound of Formula (I):

or a pharmaceutically acceptable salt or a stereoisomer thereof,wherein: X¹ is O, S, N, NR¹ or CR¹; X² is N or C; X³ is O, S, N, NR³ orCR³; X⁴ is N or CR⁴; X⁵ is N or CR⁵; X⁶ is N or CR⁶; Y is C or N; atleast one of X¹, X², X³ and Y is a heteroatom selected from N, O and S,wherein N is optionally substituted by R¹ or R³; Cy is C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, 5- to 14-membered heteroaryl, or 4- to 10-memberedheterocycloalkyl, each of which is optionally substituted with 1 to 5independently selected R⁷ substituents; R¹, R³, R⁴, R⁵ and R⁶ are eachindependently selected from H, C₁₋₄ alkyl, C₃₋₄ cycloalkyl, C₂₋₄alkenyl, C₂₋₄ alkynyl, halo, CN, OH, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄haloalkoxy, NH₂, —NH—C₁₋₄ alkyl, —N(C₁₋₄ alkyl)₂, NHOR¹⁰, C(O)R¹⁰,C(O)NR¹⁰R¹⁰, C(O)OR¹⁰, OC(O)R¹⁰, OC(O)NR¹⁰R¹⁰, NR¹⁰C(O)R¹⁰,NR¹⁰C(O)OR¹⁰, NR¹⁰C(O)NR¹⁰R¹⁰, C(═NR¹⁰)R¹⁰, C(═NR¹⁰)NR¹⁰R¹⁰,NR¹⁰C(═NR¹⁰)NR¹⁰R¹⁰, NR¹⁰S(O)R¹⁰, NR¹⁰S(O)₂R¹⁰, NR¹⁰S(O)₂NR¹⁰R¹⁰,S(O)R¹⁰, S(O)NR¹⁰R¹⁰, S(O)₂R¹⁰, and S(O)₂NR¹⁰R¹⁰, wherein each R¹⁰ isindependently selected from H and C₁₋₄ alkyl optionally substituted with1 or 2 groups independently selected from halo, OH, CN and C₁₋₄ alkoxy;and wherein the C₁₋₄ alkyl, C₃₋₄ cycloalkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyland C₁₋₄ alkoxy of R¹, R³, R⁴, R⁵ and R⁶ are each optionally substitutedwith 1 or 2 substituents independently selected from halo, OH, CN andC₁₋₄ alkoxy; R⁹ is C₁₋₄ alkyl, halo, CN, OH, cyclopropyl, C₂₋₄ alkenyl,C₂₋₄ alkynyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, NH₂,—NH—C₁₋₄ alkyl, —N(C₁₋₄ alkyl)₂, NHOR¹¹, C(O)R¹¹, C(O)NR¹¹R¹¹, C(O)OR¹¹,OC(O)R¹¹, OC(O)NR¹¹R¹¹, NR¹¹C(O)R¹¹, NR¹¹C(O)OR¹¹, NR¹¹S(O)₂R¹¹,NR¹¹S(O)₂NR¹¹R¹¹, S(O)R¹¹, S(O)NR¹¹R¹¹, S(O)₂R¹¹, and S(O)₂NR¹¹R¹¹,wherein C₁₋₄ alkyl, cyclopropyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl and C₁₋₄alkoxy of R⁹ are each optionally substituted with 1 or 2 substituentsselected from halo, OH, CN and OCH₃ and each R¹¹ is independentlyselected from H and C₁₋₄ alkyl optionally substituted with 1 or 2 halo,OH, CN or OCH₃ substituents; R⁷, R¹³ and R¹⁴ are each independentlyselected from H, halo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆haloalkyl, C₁₋₆ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-14 membered heteroaryl)-C₁₋₄ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, CN, NO₂, OR^(a), SR^(a),NHOR^(a), C(O)R^(a), C(O)NR^(a)R^(a), C(O)OR^(a), OC(O)R^(a),OC(O)NR^(a)R^(a), NHR^(a), NR^(a)R^(a), NR^(a)C(O)R^(a),NR^(a)C(O)OR^(a), NR^(a)C(O)NR^(a)R^(a), C(═NR^(a))R^(a),C(═NR^(a))NR^(a)R^(a), NR^(a)C(═NR^(a))NR^(a)R^(a), NR^(a)S(O)R^(a),NR^(a)S(O)₂R^(a), NR^(a)S(O)₂NR^(a)R^(a), S(O)R^(a), S(O)NR^(a)R^(a),S(O)₂R^(a), and S(O)₂NR^(a)R^(a), wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-14 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-14 membered heteroaryl)-C₁₋₄ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R⁷, R¹³ and R¹⁴ are eachoptionally substituted with 1, 2, 3, or 4 R^(b) substituents; or twoadjacent R⁷ substituents on the Cy ring, taken together with the atomsto which they are attached, form a fused phenyl ring, a fused 5-, 6- or7-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroarylring or a fused C₃₋₆ cycloalkyl ring, wherein the fused 5-, 6- or7-membered heterocycloalkyl ring and fused 5- or 6-membered heteroarylring each have 1-4 heteroatoms as ring members selected from N, O and Sand wherein the fused phenyl ring, fused 5-, 6- or 7-memberedheterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fusedC₃₋₆ cycloalkyl ring are each optionally substituted with 1, 2 or 3independently selected R^(b) substituents; or two R¹³ substituentsattached to the same carbon atom, taken together with the carbon atom towhich they are attached, form a C₃₋₆ cycloalkyl ring or 4-, 5-, 6- or7-membered heterocycloalkyl ring, wherein the C₃₋₆ cycloalkyl ring and4-, 5-, 6- or 7-membered heterocycloalkyl ring are each optionallysubstituted with 1, 2 or 3 independently selected R^(b) substituents;each R^(a) is independently selected from H, CN, C₁₋₆ alkyl, C₁₋₄haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl,5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 memberedheteroaryl)-C₁₋₄ alkyl-, and (4-10 membered heterocycloalkyl)-C₁₋₄alkyl-, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(a) are each optionally substitutedwith 1, 2, 3, 4, or 5 R^(d) substituents; each R^(d) is independentlyselected from C₁₋₄ alkyl, C₁₋₄ haloalkyl, halo, C₃₋₁₀ cycloalkyl, 4-10membered heterocycloalkyl, CN, NH₂, NHOR^(e), OR^(e), SR^(e), C(O)R^(e),C(O)NR^(e)R^(e), C(O)OR^(e), OC(O)R^(e), OC(O)NR^(e)R^(e), NHR^(e),NR^(e)R^(e), NR^(e)C(O)R^(e), NR^(e)C(O)NR^(e)R^(e), NR^(e)C(O)OR^(e),C(═NR^(e))NR^(e)R^(e), NR^(e)C(═NR^(e))NR′R^(e), S(O)R^(e),S(O)NR^(e)R^(e), S(O)₂R^(e), NR^(e)S(O)₂R^(e), NR^(e)S(O)₂NR^(e)R^(e),and S(O)₂NR^(e)R^(e), where in the C₁₋₄ alkyl, C₃₋₁₀ cycloalkyl and 4-10membered heterocycloalkyl of R^(d) are each further optionallysubstituted with 1-3 independently selected R^(q) substituents; eachR^(b) substituent is independently selected from halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, CN, OH, NH₂, NO₂,NHOR^(c), SR^(c), C(O)R^(c), C(O)NR^(c)R^(c), C(O)OR^(c), OC(O)R^(c),OC(O)NR^(c)R^(c), C(═NR^(c))NR^(c)R^(c), NR^(c)C(═NR^(c))NR^(c)R^(c),NHR^(c), NR^(c)R^(c), NR^(c)C(O)R^(c), NR^(c)C(O)OR^(c),NR^(c)C(O)NR^(c)R^(c), NR^(c)S(O)R^(c), NR^(c)S(O)₂R^(c),NR^(c)S(O)₂NR^(c)R^(c), S(O)R^(c), S(O)NR^(c)R^(c), S(O)₂R^(c) andS(O)₂NR^(c)R^(c); wherein the C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄haloalkoxy, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(b) are each further optionallysubstituted with 1-3 independently selected R^(d) substituents; eachR^(c) is independently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-,and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄alkyl- and (4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(c) areeach optionally substituted with 1, 2, 3, 4, or 5 R^(f) substituentsindependently selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, (4-10membered heterocycloalkyl)-C₁₋₄ alkyl-, halo, CN, NHOR^(g), OR^(g),SR^(g), C(O)R^(g), C(O)NR^(g)R^(g), C(O)OR^(g), OC(O)R^(g),OC(O)NR^(g)R^(g), NHR^(g), NR^(g)R^(g), NR^(g)C(O)R^(g),NR^(g)C(O)NR^(g)R^(g), NR^(g)C(O)OR^(g), C(═NR^(g))NR^(g)R^(g),NR^(g)C(═NR^(g))NR^(g)R^(g), S(O)R^(g), S(O)NR^(g)R^(g), S(O)₂R^(g),NR^(g)S(O)₂R^(g), NR^(g)S(O)₂NR^(g)R^(g), and S(O)₂NR^(g)R^(g); whereinthe C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl,C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-,(5-10 membered heteroaryl)-C₁₋₄ alkyl-, and (4-10 memberedheterocycloalkyl)-C₁₋₄ alkyl- of R^(f) are each optionally substitutedwith 1, 2, 3, 4, or 5 R^(n) substituents independently selected fromC₁₋₄ alkyl, C₁₋₄ haloalkyl, halo, CN, NHOR^(o), OR^(o), SR^(o),C(O)R^(o), C(O)NR^(o)R^(o), C(O)OR^(o), OC(O)R^(o), OC(O)NR^(o)R^(o),NHR^(o), NR^(o)R^(o), NR^(o)C(O)R^(o), NR^(o)C(O)NR^(o)R^(o),NR^(o)C(O)OR^(o), C(═NR^(o))NR^(o)R^(o), NR^(o)C(═NR^(o))NR^(o)R^(o),S(O)R^(o), S(O)NR^(o)R^(o), S(O)₂R^(o), NR^(o)S(O)₂R^(o),NR^(o)S(O)₂NR^(o)R^(o), and S(O)₂NR^(o)R^(o); each R^(g) isindependently selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-, C₃₋₁₀cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl-, and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl-, wherein the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, C₆₋₁₀ aryl-C₁₋₄ alkyl-,C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-10 membered heteroaryl)-C₁₋₄ alkyl- and(4-10 membered heterocycloalkyl)-C₁₋₄ alkyl- of R^(g) are eachoptionally substituted with 1-3 independently selected R^(p)substituents; or any two R^(a) substituents together with the nitrogenatom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or10-membered heterocycloalkyl group optionally substituted with 1, 2 or 3R^(h) substituents independently selected from C₁₋₆ alkyl, C₃₋₁₀cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6 memberedheteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-6 membered heteroaryl)-C₁₋₄alkyl-, (4-7 membered heterocycloalkyl)-C₁₋₄ alkyl-, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, halo, CN, OR^(i), SR^(i), NHOR^(i),C(O)R^(i), C(O)NR^(i)R^(i), C(O)OR^(i), OC(O)R^(i), OC(O)NR^(i)R^(i),NHR^(i), NR^(i)R^(i), NR^(i)C(O)R^(i), NR^(i)C(O)NR^(i)R^(i),NR^(i)C(O)OR^(i), C(═NR^(i))NR^(i)R^(i), NR^(i)C(═NR^(i))NR^(i)R^(i),S(O)R^(i), S(O)NR^(i)R^(i), S(O)₂R^(i), NR^(i)S(O)₂R^(i),NR^(i)S(O)₂NR^(i)R^(i), and S(O)₂NR^(i)R^(i), wherein the C₁₋₆ alkyl,C₃₋₁₀ cycloalkyl, 4-7 membered heterocycloalkyl, C₆₋₁₀ aryl, 5-6membered heteroaryl, C₃₋₁₀ cycloalkyl-C₁₋₄ alkyl-, (5-6 memberedheteroaryl)-C₁₋₄ alkyl-, (4-7 membered heterocycloalkyl)-C₁₋₄ alkyl- ofR^(h) are each further optionally substituted by 1, 2, or 3 substituentsindependently selected from C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or 6-memberedheteroaryl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, halo, C₁₋₄ alkyl, C₁₋₄haloalkyl, CN, NHOR^(k), OR^(k), SR^(k), C(O)R^(k), C(O)NR^(k)R^(k),C(O)OR^(k), OC(O)R^(k), OC(O)NR^(k)R^(k), NHR^(k), NR^(k)R^(k),NR^(k)C(O)R^(k), NR^(k)C(O)NR^(k)R^(k), NR^(k)C(O)OR^(k),C(═NR^(k))NR^(k)R^(k), NR^(k)C(═NR^(k))NR^(k)R^(k), S(O)R^(k),S(O)NR^(k)R^(k), S(O)₂R^(k), NR^(k)S(O)₂R^(k), NR^(k)S(O)₂NR^(k)R^(k),and S(O)₂NR^(k)R^(k); or two R^(h) groups attached to the same carbonatom of the 4- to 10-membered heterocycloalkyl taken together with thecarbon atom to which they are attached form a C₃₋₆ cycloalkyl or 4- to6-membered heterocycloalkyl having 1-2 heteroatoms as ring membersselected from O, N or S; or any two R^(c) substituents together with thenitrogen atom to which they are attached form a 4-, 5-, 6-, or7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3independently selected R^(h) substituents; or any two R^(e) substituentstogether with the nitrogen atom to which they are attached form a 4-,5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with1, 2, or 3 independently selected R^(h) substituents; or any two R^(g)substituents together with the nitrogen atom to which they are attachedform a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionallysubstituted with 1, 2, or 3 independently selected R^(h) substituents;or any two R^(o) substituents together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 independently selectedR^(h) substituents; and each R^(e), R^(i), R^(k), R^(o) or R^(p) isindependently selected from H, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl,5 or 6-membered heteroaryl, C₁₋₄ haloalkyl, C₂₋₄ alkenyl, and C₂₋₄alkynyl, wherein the C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, 5 or6-membered heteroaryl, C₂₋₄ alkenyl, and C₂₋₄ alkynyl of R^(e), R^(i),R^(k), R^(o) or R^(p) are each optionally substituted with 1, 2 or 3R^(q) substituents; each R^(q) is independently selected from OH, CN,—COOH, NH₂, halo, C₁₋₆haloalkyl, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, C₁₋₆ alkylthio, phenyl, 5-6 membered heteroaryl, 4-6membered heterocycloalkyl, C₃₋₆ cycloalkyl, NHR¹², NR¹²R¹², and C₁₋₄haloalkoxy, wherein the C₁₋₆ alkyl, phenyl, C₃₋₆ cycloalkyl, 4-6membered heterocycloalkyl, and 5-6 membered heteroaryl of R^(q) are eachoptionally substituted with halo, OH, CN, —COOH, NH₂, C₁₋₄ alkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkoxy, phenyl, C₃₋₁₀ cycloalkyl and 4-6 memberedheterocycloalkyl and each R¹² is independently C₁₋₆ alkyl;

is a single bond or a double bond to maintain ring A being aromatic; thesubscript n is an integer of 1, 2, 3, 4, 5 or 6; and when R⁹ is OH, Cyis other than 6-carbamimidoyl-1H-benzo[d]imidazol-2-yl. 2.-31.(canceled)
 32. A pharmaceutical composition comprising a compound ofclaim 1, or a pharmaceutically acceptable salt or a stereoisomerthereof, and at least one pharmaceutically acceptable carrier orexcipient.
 33. A method of inhibiting PD-1/PD-L1 interaction, saidmethod comprising administering to an individual a compound of claim 1,or a pharmaceutically acceptable salt or a stereoisomer thereof.
 34. Amethod of treating a disease or disorder associated with inhibition ofPD-1/PD-L1 interaction, said method comprising administering to apatient in need thereof a therapeutically effective amount of a compoundof claim 1, or a pharmaceutically acceptable salt or a stereoisomerthereof.
 35. The method of claim 34, wherein the disease or disorder isa viral infection or cancer.
 36. A method of enhancing, stimulatingand/or increasing the immune response in a patient, said methodcomprising administering to the patient in need thereof atherapeutically effective amount of a compound of claim 1, or apharmaceutically acceptable salt or a stereoisomer thereof.